PREFIX up: <http://purl.uniprot.org/core/>
PREFIX taxon: <http://purl.uniprot.org/taxonomy/>
PREFIX skos: <http://www.w3.org/2004/02/skos/core#>
PREFIX faldo: <http://biohackathon.org/resource/faldo#>
SELECT DISTINCT ?disease WHERE {
  ?protein up:organism taxon:9606 .
  ?protein up:enzyme ?enzyme .
  ?protein up:annotation ?variant .
  ?variant a up:Natural_Variant_Annotation .
  ?variant skos:related ?disease .
  ?variant up:range ?vrange .
  ?vrange faldo:begin ?vpos .
  ?vpos faldo:position ?pos .
  ?protein up:annotation ?activeSite .
  ?activeSite a up:Active_Site_Annotation .
  ?activeSite up:range ?arange .
  ?arange faldo:begin ?apos .
  ?apos faldo:position ?pos .
}
LIMIT 10

Got 10 rows and 1 column:
| disease      |
| ------------ |
| disease:1064 |
| disease:113  |
| disease:1238 |
| disease:1278 |
| disease:1302 |
| disease:133  |
| disease:1440 |
| disease:1541 |
| disease:1542 |
| disease:1544 |

This query efficiently finds human genetic diseases related to a natural variant located on the active site of an enzyme by matching the position integer of the variant and the active site. Example diseases found include Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1 (disease:1064), Amyotrophic lateral sclerosis 9 (disease:113), Parkinson disease 2 (disease:1238), Hyperphenylalaninemia, BH4-deficient, C (disease:1278), Butyrylcholinesterase deficiency (disease:1302), Argininosuccinic aciduria (disease:133), Cowden syndrome 1 (disease:1440), Factor VII deficiency (disease:1541), Factor XI deficiency (disease:1542), and Fabry disease (disease:1544).

[System]
You are a question answering assistant. Your job is to generate a SPARQL query to answer a given user question.

You have access to the following knowledge graphs:
uniprot at https://qlever.cs.uni-freiburg.de/api/uniprot

You can use the following SPARQL prefixes implicitly in all functions:
ECO: <http://purl.obolibrary.org/obo/ECO_
annotation: <http://purl.uniprot.org/annotation/
bibo: <http://purl.org/ontology/bibo/
busco: <http://busco.ezlab.org/schema#
chebi: <http://purl.obolibrary.org/obo/CHEBI_
citation: <http://purl.uniprot.org/citations/
cito: <http://purl.org/spar/cito/
dcat: <http://www.w3.org/ns/dcat#
dcmit: <http://purl.org/dc/dcmitype/
dcterms: <http://purl.org/dc/terms/
disease: <http://purl.uniprot.org/diseases/
embl-cds: <http://purl.uniprot.org/embl-cds/
ensembl: <http://rdf.ebi.ac.uk/resource/ensembl/
enzyme: <http://purl.uniprot.org/enzyme/
faldo: <http://biohackathon.org/resource/faldo#
foaf: <http://xmlns.com/foaf/0.1/
go: <http://purl.obolibrary.org/obo/GO_
hs: <https://hamap.expasy.org/rdf/vocab#
isoform: <http://purl.uniprot.org/isoforms/
keywords: <http://purl.uniprot.org/keywords/
location: <http://purl.uniprot.org/locations/
obo: <http://purl.obolibrary.org/obo/
oboInOwl: <http://www.geneontology.org/formats/oboInOwl#
owl: <http://www.w3.org/2002/07/owl#
patent: <http://purl.uniprot.org/EPO/
pav: <http://purl.org/pav/
position: <http://purl.uniprot.org/position/
prism: <http://prismstandard.org/namespaces/basic/2.0/
pubmed: <http://purl.uniprot.org/pubmed/
range: <http://purl.uniprot.org/range/
rdf: <http://www.w3.org/1999/02/22-rdf-syntax-ns#
rdfs: <http://www.w3.org/2000/01/rdf-schema#
rh: <http://rdf.rhea-db.org/
schema: <http://schema.org/
sd: <http://www.w3.org/ns/sparql-service-description#
sh: <http://www.w3.org/ns/shacl#
skos: <http://www.w3.org/2004/02/skos/core#
sp: <http://spinrdf.org/sp#
ssmRegion: <http://purl.uniprot.org/signatureSequenceMatch/
stato: <http://purl.obolibrary.org/obo/STATO_
taxon: <http://purl.uniprot.org/taxonomy/
tissue: <http://purl.uniprot.org/tissues/
uniparc: <http://purl.uniprot.org/uniparc/
uniprot: <http://purl.uniprot.org/uniprot/
up: <http://purl.uniprot.org/core/
voag: <http://voag.linkedmodel.org/schema/voag#
void: <http://rdfs.org/ns/void#
xsd: <http://www.w3.org/2001/XMLSchema#
dc: <http://purl.org/dc/elements/1.1/
prov: <http://www.w3.org/ns/prov#
geo: <http://www.opengis.net/ont/geosparql#
geosparql: <http://www.opengis.net/ont/geosparql#
gn: <http://www.geonames.org/ontology#
bd: <http://www.bigdata.com/rdf#
hint: <http://www.bigdata.com/queryHints#
wikibase: <http://wikiba.se/ontology#
qb: <http://purl.org/linked-data/cube#

You should follow a step-by-step approach to generate the SPARQL query:
1. Determine possible entities and properties implied by the user question.
2. Use the functions to search for entities and properties in the knowledge graphs. Where applicable, constrain the searches with already identified entities and properties.
3. Gradually build up the SPARQL query using the identified entities and properties. Start with simple queries and add more complexity as needed. Use the execute function to get feedback on intermediate queries. You can go back and forth between knowledge graph searches and SPARQL query executions to refine the query.
4. Use the answer or cancel function to finalize your answer and stop the generation process.

Additional rules:
1. Explain your thought process before and after each step and function call.
2. Do not assume or make up any entities or properties without verifying them with the knowledge graphs and functions.
3. The SPARQL query should always return the actual identifiers / IRIs of the items in its result. It additionally may return labels or other human-readable information, but they are optional and should be put within optional clauses unless explicitly requested by the user.
4. Do not stop early if there are still obvious improvements to be made to the SPARQL query. For example, keep refining your SPARQL query if its result contains irrelevant items or is missing items you expected.
5. Do not perform additional computation (e.g. filtering, sorting, calculations) on the result of the SPARQL query to determine the answer. All computation should be done solely within SPARQL.
6. For questions with a "True" or "False" answer the SPARQL query should be an ASK query.
7. Do not use 'SERVICE wikibase:label { bd:serviceParam wikibase:language ...' in SPARQL queries. It is not SPARQL standard and unsupported by the used QLever SPARQL endpoints. Use rdfs:label or similar properties to get labels instead.

[User] Find human genetic diseases that are related to a natural variant located on the active site of an enzyme.

[Assistant]
Let's break down the question:

1. We are looking for human genetic diseases.
2. These diseases should be related to a natural variant.
3. The natural variant must be located on the active site of an enzyme.

Step-by-step plan:
- Identify how "human genetic diseases" are represented in UniProt.
- Find how natural variants are linked to diseases in UniProt.
- Determine how to find variants that are located on the "active site" of an enzyme.
- Ensure the protein is an enzyme.

Let's start by searching for how "human genetic disease" is represented in UniProt.

[Tool]
Top 10 entity alternatives:
1. MalaCards human disease database (<http://purl.uniprot.org/database/MalaCards>)
2. GeneCards: human genes, protein and diseases (<http://purl.uniprot.org/database/GeneCards>)
3. 9606, also known as Homo sapiens, Humo sapiens, Homo spiens, Homo spaiens, Homo sapines (taxon:9606)
4. Disease (up:Disease)
5. 51031, also known as NECAM, Necator americanus, New World hookworm, Necator americanus Stiles, 1902, Human hookworm (taxon:51031)
6. 51028, also known as Enterobius vermicularis, Human pinworm, ENTVE (taxon:51028)
7. 3052759, also known as DeSV, Human tanzavirus, Tanzavirus daressalaamense (taxon:3052759)
8. 1867125, also known as cutavirus (human), Cutavirus (taxon:1867125)
9. 290028, also known as CVHK1, HCoV-HKU1, CoV-HKU1, Human CoV/HKU1, Human coronavirus HKU1 (taxon:290028)
10. 162145, also known as HMPV, human metapneumovirus (taxon:162145)

[Tool]
Top 10 entity alternatives:
1. Disease (up:Disease)
2. horizontal gene transfer, also known as genetic transfer, lateral gene transfer, genetic exchange (go:0009292): The introduction of genetic information into a cell to create a ...lly different individual, without production of new individuals.
3. genomic imprinting, also known as DNA imprinting, establishment of genomic imprinting, genetic imprinting (go:0071514): The establishment of epigenetic modifications (imprints) during ...erochromatin formation or differential chromatin loop formation.
4. Disease Annotation (up:Disease_Annotation): Description of the diseases associated with a deficiency of a protein.
5. 206311, also known as pink thread, Erythricium salmonicolor, pink disease, Erythricium salmonicolor (Berk. & Broome) Burds., 1985, Corticium salmonicolor Berk. & Broome, 1875 (taxon:206311)
6. 358764, also known as Border disease virus (taxon:358764)
7. 12455, also known as Borna disease virus, Borna disease virus BDV, BDV (taxon:12455)
8. 139, also known as Borrelia burgdorferi, Borreliella burgdorferi, strain B31, DSM 4680, CIP 102532 (taxon:139)
9. 64895, also known as Borrelia burgdorferi group, Borrelia burgdorferi sensu lato, Borreliella Adeolu and Gupta 2015, Lyme Disease Borrelia, Borreliella (taxon:64895)
10. 268305, also known as Bovine viral diarrhea virus (strain CP7), Bovine viral diarrhea virus strain CP7, Bovine viral diarrhea virus 1-CP7, BVDVC, Mucosal disease virus (taxon:268305)

[Tool]
Top 10 entity alternatives:
1. Natural Variation (up:Natural_Variation_Annotation)
2. Sequence Variant (up:Natural_Variant_Annotation): Authors report that sequence variants exist.
3. Splice Variant (up:Alternative_Sequence_Annotation): Description of sequence variants produced by alternative splicing.
4. 942642, also known as Biemna variantia (Bowerbank, 1858), Biemna variantia, Halichondria variantia Bowerbank, 1858, Halichondria variantia (taxon:942642)
5. 2027422, also known as Ernstia naturalis Van Soest & De Voogd, 2015, Ernstia naturalis (taxon:2027422)
6. 36351, also known as HHV-6 variant B, Human herpesvirus 6B (strain Z29), Human herpesvirus 6 strain Z29, Human herpesvirus (type 6 / strain Z29), Herpes simplex virus (type 6 / strain Z29) (taxon:36351)
7. 10370, also known as HHV6U, Human B lymphotropic virus, Human herpesvirus 6A (strain Uganda-1102), HHV-6 variant A, Human herpesvirus 6 (strain Uganda-1102) (taxon:10370)
8. 32604, also known as Human B lymphotropic virus, HHV6H, HHV-6 variant B, Human betaherpesvirus 6B, Human herpes virus 6B (taxon:32604)
9. 10369, also known as Human herpesvirus 6 (strain GS), Human herpesvirus 6A (strain GS), Human herpesvirus (type 6 / strain GS), HHV-6 variant A, HHV6G (taxon:10369)
10. 1780262, also known as Simulium naturale Davies, 1966, Simulium naturale, Simulium (Nevermannia) naturale (taxon:1780262)

[Tool]
Top 10 entity alternatives:
1. Active Site (up:Active_Site_Annotation): Amino acid(s) involved in the activity of an enzyme.
2. obsolete enzyme active site formation (go:0018307): OBSOLETE. The modification of part of an enzyme to form the active site.
3. obsolete enzyme active site form...hospho-5'-guanosine)-L-histidine (go:0045427): OBSOLETE. The transient guanylylation of peptidyl-histidine to form (phospho-5'-guanosine)-L-histidine.
4. obsolete enzyme active site form...hospho-5'-adenosine)-L-histidine (go:0051113): OBSOLETE. The transient adenylylation of peptidyl-histidine to f...dine (otherwise known as tau-AMP-histidine, tele-AMP-histidine).
5. obsolete enzyme active site form...(phospho-5'-uridine)-L-histidine (go:0051115): OBSOLETE. The transient uridylylation of peptidyl-histidine to f...dine (otherwise known as tau-UMP-histidine, tele-UMP-histidine).
6. obsolete enzyme active site formation via 1'-phospho-L-histidine (go:0018327): OBSOLETE. The transient phosphorylation of peptidyl-histidine to...otherwise known as tau-phosphohistidine, tele-phosphohistidine).
7. obsolete enzyme active site formation via 3'-phospho-L-histidine (go:0018328): OBSOLETE. The transient phosphorylation of peptidyl-histidine to...(otherwise known as pi-phosphohistidine, pros-phosphohistidine).
8. obsolete enzyme active site formation via L-2',4',5'-topaquinone (go:0018337): OBSOLETE. (Was not defined before being made obsolete).
9. obsolete enzyme active site form...-(phospho-5'-adenosine)-L-lysine (go:0018329): OBSOLETE. The transient adenylylation of lysine to form N6-(phos...L-lysine, found in the active site of DNA ligase and RNA ligase.
10. obsolete enzyme active site form...-(phospho-5'-guanosine)-L-lysine (go:0018330): OBSOLETE. The transient guanylylation of lysine to form N6-(phos...d in the guanylyltransferase active site of mRNA capping enzyme.

[Tool]
Top 10 entity alternatives:
1. Enzyme (up:Enzyme): A specific catalytic activity, defined by the Enzyme Commission ...ternational Union of Biochemistry and Molecular Biology (IUBMB).
2. mitochondrial fatty acid beta-oxidation multienzyme complex, also known as fatty acid beta-oxidation multienzyme complex, trifunctional enzyme (go:0016507): A multienzyme complex possessing three activities in two subunit...tains the acetyl-CoA C-acyltransferase (KACT)/thiolase activity.
3. methionine adenosyltransferase activity, also known as methionine S-adenosyltransferase activity, S-adenosylmethionine synthetase activity, S-adenosylmethionine synthase activity, S-adenosyl-L-methionine synthetase activity, methionine-activating enzyme (go:0004478): Catalysis of the reaction: ATP + L-methionine + H2O = phosphate + diphosphate + S-adenosyl-L-methionine.
4. N-formylglutamate deformylase activity, also known as formylglutamate deformylase activity, beta-citrylglutamate amidase activity, N-formylglutamate hydrolase activity, N-formyl-L-glutamate amidohydrolase activity, beta-citryl-L-glutamate hydrolase activity (go:0050129): Catalysis of the reaction: N-formyl-L-glutamate + H2O = L-glutamate + formate.
5. N,N-dimethylaniline monooxygenase activity, also known as 1-methyl-4-phenyl-1,2,3,6-tetrah...oxygen N-oxidoreductase activity, methylphenyltetrahydropyridine N-monooxygenase activity, dimethylaniline monooxygenase (N-oxide-forming) activity, Ziegler's enzyme, N,N-dimethylaniline,NADPH:oxygen oxidoreductase (N-oxide-forming) (go:0004499): Catalysis of the reaction: N,N-dimethylaniline + NADPH + H+ + O2 = N,N-dimethylaniline N-oxide + NADP+ + H2O.
6. muconate cycloisomerase activity, also known as cis,cis-muconate-lactonizing enzyme, muconate cycloisomerase I activity, muconate lactonizing enzyme activity, muconate lactonizing enzyme I activity, cis,cis-muconate cycloisomerase activity (go:0018849): Catalysis of the reaction: 2,5-dihydro-5-oxofuran-2-acetate = cis,cis-hexadienedioate.
7. zinc D-Ala-D-Ala carboxypeptidase activity, also known as D-alanyl-D-alanine hydrolase activity, D-alanyl-D-alanine-cleaving carboxypeptidase activity, DD-carboxypeptidase, DD-carboxypeptidase-transpeptidase activity, G enzyme (go:0009046): Catalysis of the cleavage of the D-alanyl-D-alanine bond in (Ac)2-L-lysyl-D-alanyl-D-alanine.
8. xanthine oxidase activity, also known as hypoxanthine-xanthine oxidase activity, xanthine:xanthine oxidase activity, xanthine:oxygen oxidoreductase activity, xanthine:O2 oxidoreductase activity, xanthine oxidoreductase activity (go:0004855): Catalysis of the reaction: xanthine + H2O + O2 = urate + hydrogen peroxide.
9. thiomorpholine-carboxylate dehydrogenase activity, also known as ketimine reductase activity, ketimine-reducing enzyme, thiomorpholine-3-carboxylate:NAD(P)+ 5,6-oxidoreductase activity (go:0047127): Catalysis of the reaction: NAD(P)+ + thiomorpholine-3-carboxylate = NAD(P)H + 3,4-dehydro-1,4-thiomorpholine-3-carboxylate.
10. thiosulfate dehydrogenase activity, also known as thiosulfate oxidase activity, thiosulphate dehydrogenase activity, thiosulfate:ferricytochrome-c oxidoreductase activity, thiosulfate-acceptor oxidoreductase activity, tetrathionate synthase activity (go:0050338): Catalysis of the reaction: 2 thiosulfate + 2 ferricytochrome c = tetrathionate + 2 ferrocytochrome c.

[Tool]
Top 10 property alternatives:
1. disease (up:disease): has domain Disease Annotation, has range Disease
2. member of (up:memberOf): has range Cluster (UniRef), has domain Sequence
3. common taxon (up:commonTaxon): has domain Cluster (UniRef), has range Taxon
4. strain (up:strain): has range Taxonomy rank Strain, has range Strain, has domain Taxon
5. related (skos:related)
6. organism (up:organism): The organism in which a protein occurs., has range Taxon
7. institution (up:institution): The institution at which a thesis was written., has domain Thesis Citation
8. interaction (up:interaction): has range Interaction, has domain Protein
9. some members classified with (up:someMembersClassifiedWith): Indicates which GO terms are somewhat consistently used to annotate UniProtKB members of this cluster., has domain Cluster (UniRef)
10. proteome (up:proteome)

[Tool]
Top 10 property alternatives:
1. disease (up:disease): has domain Disease Annotation, has range Disease
2. abstract (dcterms:abstract)
3. modified (dcterms:modified)
4. version (up:version)
5. distinct members (owl:distinctMembers)
6. strain (up:strain): has range Taxonomy rank Strain, has range Strain, has domain Taxon
7. scientific name (up:scientificName): has domain Taxon
8. alternativeName (up:alternativeName): A synonym of the recommended name., has range Structured_Name
9. modification (up:modification): A modification of a sequence., has domain Modified Sequence, has range Splice Variant
10. other name (up:otherName): has domain Taxon

[Tool]
Top 10 property alternatives:
1. locator (up:locator): has domain Citation
2. located in (up:locatedIn): has domain Subcellular Location Annotation
3. related location (up:relatedLocation): has domain Subcellular Location, has range Subcellular Location
4. located on (up:locatedOn): The molecule a this resource is located on., has domain Nucleotide Resource, has range Molecule
5. place of publication (up:place): The place where a publication was published. This usually includes a country name.
6. location (faldo:location)
7. version (up:version)
8. distinct members (owl:distinctMembers)
9. sequence discrepancy (up:sequenceDiscrepancy): Used when a CoDing Sequences (CDS) from the INSDC differs substa...e of the difference as a rdfs:comment linked via this predicate., has domain Nucleotide Resource
10. version info (owl:versionInfo)

[Tool]
Top 10 property alternatives:
1. annotation (up:annotation): Attaches an annotation to a resource., has range Annotation, has domain Protein
2. mapped annotation (up:mappedAnnotation): Maps annotation to a resource. Used to link annotations/comments...external non UniProt sources via Citations to UniProt resources., has range Annotation
3. version (up:version)
4. reference dataset (busco:referenceDataset)
5. version info (owl:versionInfo)
6. abstract (dcterms:abstract)
7. chainSequenceMapping (up:chainSequenceMapping): A mapping between a Sequence/Entry and aminoacids described in a PDB record., has domain Protein
8. structured name type (up:structuredNameType): All names of the protein, from commonly used to obsolete, to used in the literature.., has domain Structured_Name
9. modified (dcterms:modified)
10. sequence discrepancy (up:sequenceDiscrepancy): Used when a CoDing Sequences (CDS) from the INSDC differs substa...e of the difference as a rdfs:comment linked via this predicate., has domain Nucleotide Resource

[Tool]
Got 65,536 rows and 3 columns, showing the first 10 rows below:
| subject            | property                   | object                                                           |
| ------------------ | -------------------------- | ---------------------------------------------------------------- |
| uniprot:A0A000     | annotation (up:annotation) | <http://purl.uniprot.org/uniprot/A0A000#SIP9A1D94175498C8F4>     |
| uniprot:A0A001     | annotation (up:annotation) | <http://purl.uniprot.org/uniprot/A0A001#SIP4C13C9E517FB1E22>     |
| uniprot:A0A002     | annotation (up:annotation) | <http://purl.uniprot.org/uniprot/A0A002#SIP2F1DEBA23C70D39B>     |
| uniprot:A0A003     | annotation (up:annotation) | <http://purl.uniprot.org/uniprot/A0A003#SIP02711004F16CBB1E>     |
| uniprot:A0A004     | annotation (up:annotation) | <http://purl.uniprot.org/uniprot/A0A004#SIP1682853632AF3AAA>     |
| uniprot:A0A006     | annotation (up:annotation) | <http://purl.uniprot.org/uniprot/A0A006#SIP1F01F07BE470EBCF>     |
| uniprot:A0A007     | annotation (up:annotation) | <http://purl.uniprot.org/uniprot/A0A007#SIP088D31B5ABFBCEC4>     |
| uniprot:A0A008     | annotation (up:annotation) | <http://purl.uniprot.org/uniprot/A0A008#SIP4D8E5C96605D3E01>     |
| uniprot:A0A009     | annotation (up:annotation) | <http://purl.uniprot.org/uniprot/A0A009#SIP3D7218B6FB132237>     |
| uniprot:A0A009GKJ5 | annotation (up:annotation) | <http://purl.uniprot.org/uniprot/A0A009GKJ5#SIP4F1081D3688EBAB9> |
| ...                | ...                        | ...                                                              |

[Tool] Got no rows and 3 columns

[Tool]
Got 65,536 rows and 3 columns, showing the first 10 rows below:
| subject               | property        | object                                           |
| --------------------- | --------------- | ------------------------------------------------ |
| annotation:VAR_000005 | type (rdf:type) | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_000006 | type (rdf:type) | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_000007 | type (rdf:type) | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_000008 | type (rdf:type) | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_000009 | type (rdf:type) | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_000010 | type (rdf:type) | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_000011 | type (rdf:type) | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_000012 | type (rdf:type) | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_000013 | type (rdf:type) | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_000014 | type (rdf:type) | Sequence Variant (up:Natural_Variant_Annotation) |
| ...                   | ...             | ...                                              |

[Tool]
Got 65,536 rows and 3 columns, showing the first 10 rows below:
| subject                                                          | property        | object                                  |
| ---------------------------------------------------------------- | --------------- | --------------------------------------- |
| <http://purl.uniprot.org/uniprot/A0A004#SIP1682853632AF3AAA>     | type (rdf:type) | Active Site (up:Active_Site_Annotation) |
| <http://purl.uniprot.org/uniprot/A0A009GKJ5#SIP9C1A174B020A141E> | type (rdf:type) | Active Site (up:Active_Site_Annotation) |
| <http://purl.uniprot.org/uniprot/A0A009GR33#SIP198863E3235B00E1> | type (rdf:type) | Active Site (up:Active_Site_Annotation) |
| <http://purl.uniprot.org/uniprot/A0A009GT55#SIP51B560541B685B6B> | type (rdf:type) | Active Site (up:Active_Site_Annotation) |
| <http://purl.uniprot.org/uniprot/A0A009GTI5#SIPC4F52C23F4B394FD> | type (rdf:type) | Active Site (up:Active_Site_Annotation) |
| <http://purl.uniprot.org/uniprot/A0A009GU52#SIPE4D8FBCD559CB3EE> | type (rdf:type) | Active Site (up:Active_Site_Annotation) |
| <http://purl.uniprot.org/uniprot/A0A009GVE0#SIPBF9293F90ADC9D43> | type (rdf:type) | Active Site (up:Active_Site_Annotation) |
| <http://purl.uniprot.org/uniprot/A0A009GVE0#SIPCBA357990D1F1122> | type (rdf:type) | Active Site (up:Active_Site_Annotation) |
| <http://purl.uniprot.org/uniprot/A0A009GVF9#SIP09AE92DC73ACC1BD> | type (rdf:type) | Active Site (up:Active_Site_Annotation) |
| <http://purl.uniprot.org/uniprot/A0A009GVF9#SIP43F47F478355CCD5> | type (rdf:type) | Active Site (up:Active_Site_Annotation) |
| ...                                                              | ...             | ...                                     |

[Tool] Got no rows and 3 columns

[Tool] Got no rows and 3 columns

[Tool]
Got 65,536 rows and 3 columns, showing the first 10 rows below:
| subject            | property                   | object                                                           |
| ------------------ | -------------------------- | ---------------------------------------------------------------- |
| uniprot:A0A000     | annotation (up:annotation) | <http://purl.uniprot.org/uniprot/A0A000#SIP9A1D94175498C8F4>     |
| uniprot:A0A001     | annotation (up:annotation) | <http://purl.uniprot.org/uniprot/A0A001#SIP4C13C9E517FB1E22>     |
| uniprot:A0A002     | annotation (up:annotation) | <http://purl.uniprot.org/uniprot/A0A002#SIP2F1DEBA23C70D39B>     |
| uniprot:A0A003     | annotation (up:annotation) | <http://purl.uniprot.org/uniprot/A0A003#SIP02711004F16CBB1E>     |
| uniprot:A0A004     | annotation (up:annotation) | <http://purl.uniprot.org/uniprot/A0A004#SIP1682853632AF3AAA>     |
| uniprot:A0A006     | annotation (up:annotation) | <http://purl.uniprot.org/uniprot/A0A006#SIP1F01F07BE470EBCF>     |
| uniprot:A0A007     | annotation (up:annotation) | <http://purl.uniprot.org/uniprot/A0A007#SIP088D31B5ABFBCEC4>     |
| uniprot:A0A008     | annotation (up:annotation) | <http://purl.uniprot.org/uniprot/A0A008#SIP4D8E5C96605D3E01>     |
| uniprot:A0A009     | annotation (up:annotation) | <http://purl.uniprot.org/uniprot/A0A009#SIP3D7218B6FB132237>     |
| uniprot:A0A009GKJ5 | annotation (up:annotation) | <http://purl.uniprot.org/uniprot/A0A009GKJ5#SIP4F1081D3688EBAB9> |
| ...                | ...                        | ...                                                              |

[Tool]
Got 4 rows and 3 columns:
| subject               | property                       | object                                           |
| --------------------- | ------------------------------ | ------------------------------------------------ |
| annotation:VAR_000005 | type (rdf:type)                | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_000005 | see also (rdfs:seeAlso)        | <http://purl.uniprot.org/dbsnp/rs1047303>        |
| annotation:VAR_000005 | range (up:range)               | range:22572098353770542tt367tt367                |
| annotation:VAR_000005 | substitution (up:substitution) | N                                                |

[Tool]
Got 4 rows and 3 columns:
| subject               | property                       | object                                           |
| --------------------- | ------------------------------ | ------------------------------------------------ |
| annotation:VAR_000005 | type (rdf:type)                | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_000005 | see also (rdfs:seeAlso)        | <http://purl.uniprot.org/dbsnp/rs1047303>        |
| annotation:VAR_000005 | range (up:range)               | range:22572098353770542tt367tt367                |
| annotation:VAR_000005 | substitution (up:substitution) | N                                                |

[Tool]
Got 4 rows and 3 columns:
| subject               | property                       | object                                           |
| --------------------- | ------------------------------ | ------------------------------------------------ |
| annotation:VAR_000005 | type (rdf:type)                | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_000005 | see also (rdfs:seeAlso)        | <http://purl.uniprot.org/dbsnp/rs1047303>        |
| annotation:VAR_000005 | range (up:range)               | range:22572098353770542tt367tt367                |
| annotation:VAR_000005 | substitution (up:substitution) | N                                                |

[Tool]
Got 7,128 rows and 3 columns, showing the first 10 rows below:
| subject                                                          | property             | object       |
| ---------------------------------------------------------------- | -------------------- | ------------ |
| <http://purl.uniprot.org/uniprot/A0A1B0GTQ4#SIPBF56060343C4B6EA> | disease (up:disease) | disease:6467 |
| <http://purl.uniprot.org/uniprot/A0A1B0GTW7#SIPEEB7828FF8F067D1> | disease (up:disease) | disease:6243 |
| <http://purl.uniprot.org/uniprot/A0A1W2PR82#SIPA11C94E16002C346> | disease (up:disease) | disease:5692 |
| <http://purl.uniprot.org/uniprot/A0AVF1#SIP8B1CBE4835BD3A28>     | disease (up:disease) | disease:6257 |
| <http://purl.uniprot.org/uniprot/A0PJY2#SIPF4BF70D94C2C29EA>     | disease (up:disease) | disease:4228 |
| <http://purl.uniprot.org/uniprot/A0PK11#SIP659C3FAAC97390B7>     | disease (up:disease) | disease:6028 |
| <http://purl.uniprot.org/uniprot/A1A4Y4#SIP8942DD15BC1AC1E3>     | disease (up:disease) | disease:3080 |
| <http://purl.uniprot.org/uniprot/A1L188#SIP9CC2ACF6A8B8C266>     | disease (up:disease) | disease:5760 |
| <http://purl.uniprot.org/uniprot/A1X283#SIP6C9655F380BA4CDA>     | disease (up:disease) | disease:2812 |
| <http://purl.uniprot.org/uniprot/A1XBS5#SIP851DD6190EA4CCB3>     | disease (up:disease) | disease:5433 |
| ...                                                              | ...                  | ...          |

[Tool]
Got 9 rows and 3 columns:
| subject      | property                    | object                                                              |
| ------------ | --------------------------- | ------------------------------------------------------------------- |
| disease:6467 | type (rdf:type)             | Disease (up:Disease)                                                |
| disease:6467 | see also (rdfs:seeAlso)     | <http://id.nlm.nih.gov/mesh/D009135>                                |
| disease:6467 | pref label (skos:prefLabel) | Carey-Fineman-Ziter syndrome 2                                      |
| disease:6467 | comment (rdfs:comment)      | An autosomal recessive disorder ...onia, and progressive scoliosis. |
| disease:6467 | Mnemonic (up:mnemonic)      | CFZS2                                                               |
| disease:6467 | see also (rdfs:seeAlso)     | <http://id.nlm.nih.gov/mesh/D010855>                                |
| disease:6467 | see also (rdfs:seeAlso)     | <http://id.nlm.nih.gov/mesh/D020331>                                |
| disease:6467 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/medgen/CN315603>                           |
| disease:6467 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/mim/619941>                                |

[Tool]
Got 65,536 rows and 3 columns, showing the first 10 rows below:
| subject                                     | property               | object            |
| ------------------------------------------- | ---------------------- | ----------------- |
| <http://purl.uniprot.org/EMBL_CON/AAB03340> | organism (up:organism) | 9606 (taxon:9606) |
| <http://purl.uniprot.org/EMBL_CON/AAB03341> | organism (up:organism) | 9606 (taxon:9606) |
| <http://purl.uniprot.org/EMBL_CON/AAB03342> | organism (up:organism) | 9606 (taxon:9606) |
| <http://purl.uniprot.org/EMBL_CON/AAB03343> | organism (up:organism) | 9606 (taxon:9606) |
| <http://purl.uniprot.org/EMBL_CON/AAB03344> | organism (up:organism) | 9606 (taxon:9606) |
| <http://purl.uniprot.org/EMBL_CON/AAB03345> | organism (up:organism) | 9606 (taxon:9606) |
| <http://purl.uniprot.org/EMBL_CON/AAB03346> | organism (up:organism) | 9606 (taxon:9606) |
| <http://purl.uniprot.org/EMBL_CON/AAB06448> | organism (up:organism) | 9606 (taxon:9606) |
| <http://purl.uniprot.org/EMBL_CON/AAB06449> | organism (up:organism) | 9606 (taxon:9606) |
| <http://purl.uniprot.org/EMBL_CON/AAB18828> | organism (up:organism) | 9606 (taxon:9606) |
| ...                                         | ...                    | ...               |

[Tool]
Got 8,779 rows and 3 columns, showing the first 10 rows below:
| subject                      | property        | object             |
| ---------------------------- | --------------- | ------------------ |
| 1.-.-.- (enzyme:1.-.-.-)     | type (rdf:type) | Enzyme (up:Enzyme) |
| 1.1.-.- (enzyme:1.1.-.-)     | type (rdf:type) | Enzyme (up:Enzyme) |
| 1.1.1.- (enzyme:1.1.1.-)     | type (rdf:type) | Enzyme (up:Enzyme) |
| 1.1.1.1 (enzyme:1.1.1.1)     | type (rdf:type) | Enzyme (up:Enzyme) |
| 1.1.1.10 (enzyme:1.1.1.10)   | type (rdf:type) | Enzyme (up:Enzyme) |
| 1.1.1.100 (enzyme:1.1.1.100) | type (rdf:type) | Enzyme (up:Enzyme) |
| 1.1.1.101 (enzyme:1.1.1.101) | type (rdf:type) | Enzyme (up:Enzyme) |
| 1.1.1.102 (enzyme:1.1.1.102) | type (rdf:type) | Enzyme (up:Enzyme) |
| 1.1.1.103 (enzyme:1.1.1.103) | type (rdf:type) | Enzyme (up:Enzyme) |
| 1.1.1.104 (enzyme:1.1.1.104) | type (rdf:type) | Enzyme (up:Enzyme) |
| ...                          | ...             | ...                |

[Assistant]
Here’s my plan:
- We need to find human proteins (taxon:9606) that are enzymes (up:Enzyme).
- These proteins should have a natural variant annotation (up:Natural_Variant_Annotation).
- The variant should be located at an active site (up:Active_Site_Annotation).
- The variant should be associated with a disease (up:disease).
- We want to return the disease IRIs.

To do this, I will:
- Join proteins with organism human.
- Join proteins with enzyme annotation.
- Join proteins with natural variant annotation.
- Join proteins with active site annotation.
- Join variants with disease annotation.

Now, I will write a SPARQL query that attempts to combine these constraints.

[Tool]
SPARQL execution failed:
Tried to allocate 48.5 GB, but only 18.2 GB were available. Clear the cache or allow more memory for QLever during startup

[Assistant]
The query I attempted was too complex for the endpoint to handle due to memory constraints. To address this, I will simplify the query and focus on a stepwise approach, first checking if we can find natural variants that overlap with active site annotations in human enzymes, then join with disease associations.

Let me first check if there are any proteins in humans that are enzymes and have both a natural variant and an active site annotation.

[Tool] Got no rows and 1 columns

[Tool]
Got 50 rows and 1 column, showing the first 5 and last 5 rows below:
| protein            |
| ------------------ |
| uniprot:A0A1B0GTW7 |
| uniprot:A0AVT1     |
| uniprot:A1KZ92     |
| uniprot:A1L453     |
| uniprot:A2A3K4     |
| ...                |
| uniprot:O14522     |
| uniprot:O14556     |
| uniprot:O14578     |
| uniprot:O14638     |
| uniprot:O14672     |

[Tool]
Got 10 rows and 3 columns:
| protein            | variant               | activeSite                                                       |
| ------------------ | --------------------- | ---------------------------------------------------------------- |
| uniprot:A0A1B0GTW7 | annotation:VAR_086199 | <http://purl.uniprot.org/uniprot/A0A1B0GTW7#SIP1D4E68EC4F84FC9E> |
| uniprot:A0A1B0GTW7 | annotation:VAR_086200 | <http://purl.uniprot.org/uniprot/A0A1B0GTW7#SIP1D4E68EC4F84FC9E> |
| uniprot:A0A1B0GTW7 | annotation:VAR_086201 | <http://purl.uniprot.org/uniprot/A0A1B0GTW7#SIP1D4E68EC4F84FC9E> |
| uniprot:A0A1B0GTW7 | annotation:VAR_086202 | <http://purl.uniprot.org/uniprot/A0A1B0GTW7#SIP1D4E68EC4F84FC9E> |
| uniprot:A0A1B0GTW7 | annotation:VAR_086203 | <http://purl.uniprot.org/uniprot/A0A1B0GTW7#SIP1D4E68EC4F84FC9E> |
| uniprot:A0A1B0GTW7 | annotation:VAR_086204 | <http://purl.uniprot.org/uniprot/A0A1B0GTW7#SIP1D4E68EC4F84FC9E> |
| uniprot:A0A1B0GTW7 | annotation:VAR_086205 | <http://purl.uniprot.org/uniprot/A0A1B0GTW7#SIP1D4E68EC4F84FC9E> |
| uniprot:A0A1B0GTW7 | annotation:VAR_086206 | <http://purl.uniprot.org/uniprot/A0A1B0GTW7#SIP1D4E68EC4F84FC9E> |
| uniprot:A0AVT1     | annotation:VAR_030594 | <http://purl.uniprot.org/uniprot/A0AVT1#SIP1C79E1F30FD77728>     |
| uniprot:A1KZ92     | annotation:VAR_050488 | <http://purl.uniprot.org/uniprot/A1KZ92#SIP5CD0C22C194AD41D>     |

[Tool]
Got 6 rows and 3 columns:
| subject               | property                       | object                                           |
| --------------------- | ------------------------------ | ------------------------------------------------ |
| annotation:VAR_086199 | type (rdf:type)                | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_086199 | see also (rdfs:seeAlso)        | <http://purl.uniprot.org/dbsnp/rs553352307>      |
| annotation:VAR_086199 | comment (rdfs:comment)         | In HTX12; uncertain significance.                |
| annotation:VAR_086199 | range (up:range)               | range:-9218581325671703506tt31tt31               |
| annotation:VAR_086199 | substitution (up:substitution) | F                                                |
| annotation:VAR_086199 | related (skos:related)         | disease:6243                                     |

[Tool]
Got 8 rows and 3 columns:
| subject      | property                    | object                                                              |
| ------------ | --------------------------- | ------------------------------------------------------------------- |
| disease:6243 | type (rdf:type)             | Disease (up:Disease)                                                |
| disease:6243 | see also (rdfs:seeAlso)     | <http://id.nlm.nih.gov/mesh/D059446>                                |
| disease:6243 | pref label (skos:prefLabel) | Heterotaxy, visceral, 12, autosomal                                 |
| disease:6243 | comment (rdfs:comment)      | A form of visceral heterotaxy, a...eritance is autosomal recessive. |
| disease:6243 | Mnemonic (up:mnemonic)      | HTX12                                                               |
| disease:6243 | see also (rdfs:seeAlso)     | 1056 (keywords:1056)                                                |
| disease:6243 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/medgen/CN306198>                           |
| disease:6243 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/mim/619702>                                |

[Tool]
Got 4 rows and 3 columns:
| subject               | property                       | object                                           |
| --------------------- | ------------------------------ | ------------------------------------------------ |
| annotation:VAR_030594 | type (rdf:type)                | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_030594 | see also (rdfs:seeAlso)        | <http://purl.uniprot.org/dbsnp/rs10010188>       |
| annotation:VAR_030594 | range (up:range)               | range:18348930665558318tt224tt224                |
| annotation:VAR_030594 | substitution (up:substitution) | T                                                |

[Tool]
Got 4 rows and 3 columns:
| subject               | property                       | object                                           |
| --------------------- | ------------------------------ | ------------------------------------------------ |
| annotation:VAR_050488 | type (rdf:type)                | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_050488 | see also (rdfs:seeAlso)        | <http://purl.uniprot.org/dbsnp/rs7833909>        |
| annotation:VAR_050488 | range (up:range)               | range:18350073192198702tt343tt343                |
| annotation:VAR_050488 | substitution (up:substitution) | T                                                |

[Tool]
Got 5 rows and 3 columns:
| subject               | property                       | object                                           |
| --------------------- | ------------------------------ | ------------------------------------------------ |
| annotation:VAR_086200 | type (rdf:type)                | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_086200 | comment (rdfs:comment)         | In HTX12.                                        |
| annotation:VAR_086200 | range (up:range)               | range:-9218581325671703506tt191tt788             |
| annotation:VAR_086200 | substitution (up:substitution) |                                                  |
| annotation:VAR_086200 | related (skos:related)         | disease:6243                                     |

[Tool]
Got 5 rows and 3 columns:
| subject               | property                       | object                                           |
| --------------------- | ------------------------------ | ------------------------------------------------ |
| annotation:VAR_086201 | type (rdf:type)                | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_086201 | comment (rdfs:comment)         | In HTX12; uncertain significance.                |
| annotation:VAR_086201 | range (up:range)               | range:-9218581325671703506tt324tt324             |
| annotation:VAR_086201 | substitution (up:substitution) | S                                                |
| annotation:VAR_086201 | related (skos:related)         | disease:6243                                     |

[Tool]
Got 5 rows and 3 columns:
| subject               | property                       | object                                           |
| --------------------- | ------------------------------ | ------------------------------------------------ |
| annotation:VAR_086202 | type (rdf:type)                | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_086202 | comment (rdfs:comment)         | In HTX12.                                        |
| annotation:VAR_086202 | range (up:range)               | range:-9218581325671703506tt346tt788             |
| annotation:VAR_086202 | substitution (up:substitution) |                                                  |
| annotation:VAR_086202 | related (skos:related)         | disease:6243                                     |

[Tool]
Got 6 rows and 3 columns:
| subject               | property                       | object                                           |
| --------------------- | ------------------------------ | ------------------------------------------------ |
| annotation:VAR_086203 | type (rdf:type)                | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_086203 | see also (rdfs:seeAlso)        | <http://purl.uniprot.org/dbsnp/rs183023758>      |
| annotation:VAR_086203 | comment (rdfs:comment)         | In HTX12; uncertain significance.                |
| annotation:VAR_086203 | range (up:range)               | range:-9218581325671703506tt384tt384             |
| annotation:VAR_086203 | substitution (up:substitution) | L                                                |
| annotation:VAR_086203 | related (skos:related)         | disease:6243                                     |

[Tool]
Got 6 rows and 3 columns:
| subject               | property                       | object                                           |
| --------------------- | ------------------------------ | ------------------------------------------------ |
| annotation:VAR_086204 | type (rdf:type)                | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_086204 | see also (rdfs:seeAlso)        | <http://purl.uniprot.org/dbsnp/rs2140282332>     |
| annotation:VAR_086204 | comment (rdfs:comment)         | In HTX12; uncertain significance.                |
| annotation:VAR_086204 | range (up:range)               | range:-9218581325671703506tt389tt389             |
| annotation:VAR_086204 | substitution (up:substitution) | I                                                |
| annotation:VAR_086204 | related (skos:related)         | disease:6243                                     |

[Tool]
Got 5 rows and 3 columns:
| subject               | property                       | object                                           |
| --------------------- | ------------------------------ | ------------------------------------------------ |
| annotation:VAR_086205 | type (rdf:type)                | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_086205 | comment (rdfs:comment)         | In HTX12; uncertain significance.                |
| annotation:VAR_086205 | range (up:range)               | range:-9218581325671703506tt456tt456             |
| annotation:VAR_086205 | substitution (up:substitution) |                                                  |
| annotation:VAR_086205 | related (skos:related)         | disease:6243                                     |

[Tool]
Got 5 rows and 3 columns:
| subject               | property                       | object                                           |
| --------------------- | ------------------------------ | ------------------------------------------------ |
| annotation:VAR_086206 | type (rdf:type)                | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_086206 | comment (rdfs:comment)         | In HTX12; uncertain significance.                |
| annotation:VAR_086206 | range (up:range)               | range:-9218581325671703506tt469tt469             |
| annotation:VAR_086206 | substitution (up:substitution) | P                                                |
| annotation:VAR_086206 | related (skos:related)         | disease:6243                                     |

[Tool]
Got 143 rows and 3 columns, showing the first 10 rows below:
| subject            | property                              | object                                                                                |
| ------------------ | ------------------------------------- | ----------------------------------------------------------------------------------------- |
| uniprot:A0A1B0GTW7 | type (rdf:type)                       | Protein (up:Protein)                                                                      |
| uniprot:A0A1B0GTW7 | see also (rdfs:seeAlso)               | <http://nextprot.org/rdf/entry/NX_A0A1B0GTW7>                                             |
| uniprot:A0A1B0GTW7 | modified date (up:modified)           | 2025-02-05 (xsd:date)                                                                     |
| uniprot:A0A1B0GTW7 | version (up:version)                  | 1 (xsd:int)                                                                               |
| uniprot:A0A1B0GTW7 | organism (up:organism)                | 9606 (taxon:9606)                                                                         |
| uniprot:A0A1B0GTW7 | created (up:created)                  | 2018-09-12 (xsd:date)                                                                     |
| uniprot:A0A1B0GTW7 | attribution (up:attribution)          | <http://purl.uniprot.org/uniprot/A0A1B0GTW7#attribution-04B878E6C468E9C3B2C2FC6E7C09A733> |
| uniprot:A0A1B0GTW7 | reported version (up:reportedVersion) | 1 (xsd:int)                                                                               |
| uniprot:A0A1B0GTW7 | encoded by (up:encodedBy)             | <http://purl.uniprot.org/uniprot/A0A1B0GTW7#gene-MD5272CD7D0D8DCA0445CAD6F8D9223BFF1>     |
| uniprot:A0A1B0GTW7 | proteome (up:proteome)                | <http://purl.uniprot.org/proteomes/UP000005640#Chromosome%2014>                           |
| ...                | ...                                   | ...                                                                                |

[Tool]
Got 2 rows and 3 columns:
| subject                                                          | property         | object                                  |
| ---------------------------------------------------------------- | ---------------- | --------------------------------------- |
| <http://purl.uniprot.org/uniprot/A0A1B0GTW7#SIP1D4E68EC4F84FC9E> | type (rdf:type)  | Active Site (up:Active_Site_Annotation) |
| <http://purl.uniprot.org/uniprot/A0A1B0GTW7#SIP1D4E68EC4F84FC9E> | range (up:range) | range:-9218581325671703506tt306tt306    |

[Tool]
Got 6 rows and 3 columns:
| subject               | property                       | object                                           |
| --------------------- | ------------------------------ | ------------------------------------------------ |
| annotation:VAR_086199 | type (rdf:type)                | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_086199 | see also (rdfs:seeAlso)        | <http://purl.uniprot.org/dbsnp/rs553352307>      |
| annotation:VAR_086199 | comment (rdfs:comment)         | In HTX12; uncertain significance.                |
| annotation:VAR_086199 | range (up:range)               | range:-9218581325671703506tt31tt31               |
| annotation:VAR_086199 | substitution (up:substitution) | F                                                |
| annotation:VAR_086199 | related (skos:related)         | disease:6243                                     |

[Tool]
Got 5 rows and 3 columns:
| subject               | property                       | object                                           |
| --------------------- | ------------------------------ | ------------------------------------------------ |
| annotation:VAR_086200 | type (rdf:type)                | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_086200 | comment (rdfs:comment)         | In HTX12.                                        |
| annotation:VAR_086200 | range (up:range)               | range:-9218581325671703506tt191tt788             |
| annotation:VAR_086200 | substitution (up:substitution) |                                                  |
| annotation:VAR_086200 | related (skos:related)         | disease:6243                                     |

[Tool]
Got 5 rows and 3 columns:
| subject               | property                       | object                                           |
| --------------------- | ------------------------------ | ------------------------------------------------ |
| annotation:VAR_086201 | type (rdf:type)                | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_086201 | comment (rdfs:comment)         | In HTX12; uncertain significance.                |
| annotation:VAR_086201 | range (up:range)               | range:-9218581325671703506tt324tt324             |
| annotation:VAR_086201 | substitution (up:substitution) | S                                                |
| annotation:VAR_086201 | related (skos:related)         | disease:6243                                     |

[Tool]
Got 5 rows and 3 columns:
| subject               | property                       | object                                           |
| --------------------- | ------------------------------ | ------------------------------------------------ |
| annotation:VAR_086202 | type (rdf:type)                | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_086202 | comment (rdfs:comment)         | In HTX12.                                        |
| annotation:VAR_086202 | range (up:range)               | range:-9218581325671703506tt346tt788             |
| annotation:VAR_086202 | substitution (up:substitution) |                                                  |
| annotation:VAR_086202 | related (skos:related)         | disease:6243                                     |

[Tool]
Got 6 rows and 3 columns:
| subject               | property                       | object                                           |
| --------------------- | ------------------------------ | ------------------------------------------------ |
| annotation:VAR_086203 | type (rdf:type)                | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_086203 | see also (rdfs:seeAlso)        | <http://purl.uniprot.org/dbsnp/rs183023758>      |
| annotation:VAR_086203 | comment (rdfs:comment)         | In HTX12; uncertain significance.                |
| annotation:VAR_086203 | range (up:range)               | range:-9218581325671703506tt384tt384             |
| annotation:VAR_086203 | substitution (up:substitution) | L                                                |
| annotation:VAR_086203 | related (skos:related)         | disease:6243                                     |

[Tool]
Got 6 rows and 3 columns:
| subject               | property                       | object                                           |
| --------------------- | ------------------------------ | ------------------------------------------------ |
| annotation:VAR_086204 | type (rdf:type)                | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_086204 | see also (rdfs:seeAlso)        | <http://purl.uniprot.org/dbsnp/rs2140282332>     |
| annotation:VAR_086204 | comment (rdfs:comment)         | In HTX12; uncertain significance.                |
| annotation:VAR_086204 | range (up:range)               | range:-9218581325671703506tt389tt389             |
| annotation:VAR_086204 | substitution (up:substitution) | I                                                |
| annotation:VAR_086204 | related (skos:related)         | disease:6243                                     |

[Tool]
Got 5 rows and 3 columns:
| subject               | property                       | object                                           |
| --------------------- | ------------------------------ | ------------------------------------------------ |
| annotation:VAR_086205 | type (rdf:type)                | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_086205 | comment (rdfs:comment)         | In HTX12; uncertain significance.                |
| annotation:VAR_086205 | range (up:range)               | range:-9218581325671703506tt456tt456             |
| annotation:VAR_086205 | substitution (up:substitution) |                                                  |
| annotation:VAR_086205 | related (skos:related)         | disease:6243                                     |

[Tool]
Got 5 rows and 3 columns:
| subject               | property                       | object                                           |
| --------------------- | ------------------------------ | ------------------------------------------------ |
| annotation:VAR_086206 | type (rdf:type)                | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_086206 | comment (rdfs:comment)         | In HTX12; uncertain significance.                |
| annotation:VAR_086206 | range (up:range)               | range:-9218581325671703506tt469tt469             |
| annotation:VAR_086206 | substitution (up:substitution) | P                                                |
| annotation:VAR_086206 | related (skos:related)         | disease:6243                                     |

[Tool]
Got 2 rows and 3 columns:
| subject                                                          | property         | object                                  |
| ---------------------------------------------------------------- | ---------------- | --------------------------------------- |
| <http://purl.uniprot.org/uniprot/A0A1B0GTW7#SIP1D4E68EC4F84FC9E> | type (rdf:type)  | Active Site (up:Active_Site_Annotation) |
| <http://purl.uniprot.org/uniprot/A0A1B0GTW7#SIP1D4E68EC4F84FC9E> | range (up:range) | range:-9218581325671703506tt306tt306    |

[Assistant]
After step-by-step exploration, here is a concrete example that answers your question:

- Human protein: uniprot:A0A1B0GTW7
- This protein has several natural variants (e.g., annotation:VAR_086199, annotation:VAR_086200, etc.).
- These variants are associated with the disease Heterotaxy, visceral, 12, autosomal (disease:6243).
- The protein also has an active site annotation at range:-9218581325671703506tt306tt306.
- The variants are located near or at the active site, as indicated by the overlapping or close range values.

Now, I will provide a SPARQL query that finds human genetic diseases related to a natural variant located on the active site of an enzyme, based on the above pattern.

Here is the final SPARQL query and answer:

[Tool] Stopped generation process

[User]
Feedback (status=retry):
The SPARQL query is too resource-intensive and failed due to memory constraints. The query attempts to join all natural variants and active sites for all human proteins and then filter for those with matching ranges, which is likely to produce a very large intermediate result. To improve, consider:

1. Adding more specific constraints to reduce the number of candidate proteins, variants, or active sites processed (e.g., filter for proteins already known to be enzymes, or limit to variants already linked to diseases).
2. Instead of joining on exact range equality, consider whether a more efficient spatial overlap or containment check is possible, or whether a precomputed relation exists.
3. If possible, split the query into smaller parts or use subqueries to reduce intermediate result size.

The current query cannot be executed as is and needs to be reworked for efficiency.

[Assistant]
Thank you for the feedback. To address the resource issue, I will:

1. Restrict the search to natural variants that are already linked to a disease (using skos:related or up:disease).
2. Limit to proteins that are enzymes (using up:enzyme or a up:Enzyme if available).
3. Avoid joining all ranges; instead, I will look for variants and active sites that share the same range only within the same protein, and limit the number of results.

Let me first check if the enzyme property is directly available on the protein, which would allow us to filter for enzymes more efficiently.

[Tool]
Top 10 property alternatives:
1. enzyme (up:enzyme): The catalytic activity associated with a protein. or part of a protein., has range Enzyme
2. organism (up:organism): The organism in which a protein occurs., has range Taxon
3. proteome (up:proteome)
4. type (rdf:type)
5. sequence (up:sequence): An amino acid sequence., has range Sequence
6. label (rdfs:label)
7. annotation (up:annotation): Attaches an annotation to a resource., has range Annotation, has domain Protein
8. created (up:created): The date a resource was created.
9. version (up:version)
10. citation (up:citation): A publication from which data was extracted, or which contains additional information., has range Citation

No other items found

[Tool]
Got 1 row and 3 columns:
| subject            | property           | object                     |
| ------------------ | ------------------ | -------------------------- |
| uniprot:A0A1B0GTW7 | enzyme (up:enzyme) | 3.4.24.- (enzyme:3.4.24.-) |

[Tool]
Got 65,536 rows and 3 columns, showing the first 10 rows below:
| subject            | property           | object                       |
| ------------------ | ------------------ | ---------------------------- |
| uniprot:A0A000     | enzyme (up:enzyme) | 2.3.1.47 (enzyme:2.3.1.47)   |
| uniprot:A0A004     | enzyme (up:enzyme) | 6.3.5.4 (enzyme:6.3.5.4)     |
| uniprot:A0A009GN48 | enzyme (up:enzyme) | 5.6.2.4 (enzyme:5.6.2.4)     |
| uniprot:A0A009GNX9 | enzyme (up:enzyme) | 5.3.3.4 (enzyme:5.3.3.4)     |
| uniprot:A0A009GPN5 | enzyme (up:enzyme) | 2.3.1.109 (enzyme:2.3.1.109) |
| uniprot:A0A009GPX6 | enzyme (up:enzyme) | 2.1.1.72 (enzyme:2.1.1.72)   |
| uniprot:A0A009GQ90 | enzyme (up:enzyme) | 1.1.1.85 (enzyme:1.1.1.85)   |
| uniprot:A0A009GQN0 | enzyme (up:enzyme) | 2.7.2.8 (enzyme:2.7.2.8)     |
| uniprot:A0A009GQP5 | enzyme (up:enzyme) | 2.3.2.29 (enzyme:2.3.2.29)   |
| uniprot:A0A009GR33 | enzyme (up:enzyme) | 3.5.4.4 (enzyme:3.5.4.4)     |
| ...                | ...                | ...                          |

[Tool]
Got 100 rows and 3 columns, showing the first 5 and last 5 rows below:
| protein            | variant               | disease      |
| ------------------ | --------------------- | ------------ |
| uniprot:A0A1B0GTW7 | annotation:VAR_086199 | disease:6243 |
| uniprot:A0A1B0GTW7 | annotation:VAR_086200 | disease:6243 |
| uniprot:A0A1B0GTW7 | annotation:VAR_086201 | disease:6243 |
| uniprot:A0A1B0GTW7 | annotation:VAR_086202 | disease:6243 |
| uniprot:A0A1B0GTW7 | annotation:VAR_086203 | disease:6243 |
| ...                | ...                   | ...          |
| uniprot:O00116     | annotation:VAR_025896 | disease:1003 |
| uniprot:O00116     | annotation:VAR_066929 | disease:1003 |
| uniprot:O00116     | annotation:VAR_066930 | disease:1003 |
| uniprot:O00116     | annotation:VAR_066931 | disease:1003 |
| uniprot:O00142     | annotation:VAR_019419 | disease:2018 |

[Tool]
Got 20 rows and 4 columns, showing the first 5 and last 5 rows below:
| protein        | variant               | activeSite                                                   | disease      |
| -------------- | --------------------- | ------------------------------------------------------------ | ------------ |
| uniprot:O14773 | annotation:VAR_009612 | <http://purl.uniprot.org/uniprot/O14773#SIP8DF7F8B8F67305BC> | disease:811  |
| uniprot:O43520 | annotation:VAR_043057 | <http://purl.uniprot.org/uniprot/O43520#SIP31820FE0EF6D01E0> | disease:185  |
| uniprot:O60260 | annotation:VAR_019765 | <http://purl.uniprot.org/uniprot/O60260#SIP2429AB25846E8D36> | disease:1238 |
| uniprot:P00480 | annotation:VAR_004934 | <http://purl.uniprot.org/uniprot/P00480#SIPD93355A1256BA343> | disease:883  |
| uniprot:P00480 | annotation:VAR_004935 | <http://purl.uniprot.org/uniprot/P00480#SIPD93355A1256BA343> | disease:883  |
| ...            | ...                   | ...                                                          | ...          |
| uniprot:P06276 | annotation:VAR_040024 | <http://purl.uniprot.org/uniprot/P06276#SIP43B15FC855F70FD0> | disease:1302 |
| uniprot:P06280 | annotation:VAR_000468 | <http://purl.uniprot.org/uniprot/P06280#SIPDDC6DB152087AC33> | disease:1544 |
| uniprot:P06280 | annotation:VAR_012394 | <http://purl.uniprot.org/uniprot/P06280#SIPF402416D1D3613D5> | disease:1544 |
| uniprot:P06744 | annotation:VAR_002532 | <http://purl.uniprot.org/uniprot/P06744#SIP09531CCDD7C9CBF0> | disease:1729 |
| uniprot:P06858 | annotation:VAR_004217 | <http://purl.uniprot.org/uniprot/P06858#SIPAEFE6F72182DA4B6> | disease:1911 |

[Tool]
SPARQL execution failed:
Tried to allocate 48.5 GB, but only 2 GB were available. Clear the cache or allow more memory for QLever during startup

[Tool]
Got 10 rows and 1 column:
| disease      |
| ------------ |
| disease:1064 |
| disease:113  |
| disease:1238 |
| disease:1278 |
| disease:1302 |
| disease:133  |
| disease:1440 |
| disease:1541 |
| disease:1542 |
| disease:1544 |

[Tool]
Got 9 rows and 3 columns:
| subject      | property                    | object                                                              |
| ------------ | --------------------------- | ------------------------------------------------------------------- |
| disease:1064 | type (rdf:type)             | Disease (up:Disease)                                                |
| disease:1064 | see also (rdfs:seeAlso)     | <http://id.nlm.nih.gov/mesh/D002524>                                |
| disease:1064 | pref label (skos:prefLabel) | Spinocerebellar ataxia, autosoma...essive, with axonal neuropathy 1 |
| disease:1064 | comment (rdfs:comment)      | A form of spinocerebellar ataxia...iduals have normal intelligence. |
| disease:1064 | Mnemonic (up:mnemonic)      | SCAN1                                                               |
| disease:1064 | see also (rdfs:seeAlso)     | <http://id.nlm.nih.gov/mesh/D013132>                                |
| disease:1064 | see also (rdfs:seeAlso)     | 523 (keywords:523)                                                  |
| disease:1064 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/medgen/C1846574>                           |
| disease:1064 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/mim/607250>                                |

[Tool]
Got 8 rows and 3 columns:
| subject     | property                    | object                                                              |
| ----------- | --------------------------- | ------------------------------------------------------------------- |
| disease:113 | type (rdf:type)             | Disease (up:Disease)                                                |
| disease:113 | see also (rdfs:seeAlso)     | <http://id.nlm.nih.gov/mesh/D000690>                                |
| disease:113 | pref label (skos:prefLabel) | Amyotrophic lateral sclerosis 9                                     |
| disease:113 | comment (rdfs:comment)      | A neurodegenerative disorder aff...inherited in 5-10% of the cases. |
| disease:113 | Mnemonic (up:mnemonic)      | ALS9                                                                |
| disease:113 | see also (rdfs:seeAlso)     | 36 (keywords:36)                                                    |
| disease:113 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/medgen/C2678468>                           |
| disease:113 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/mim/611895>                                |

[Tool]
Got 17 rows and 3 columns, showing the first 10 rows below:
| subject      | property                    | object                                                              |
| ------------ | --------------------------- | ------------------------------------------------------------------- |
| disease:1238 | type (rdf:type)             | Disease (up:Disease)                                                |
| disease:1238 | see also (rdfs:seeAlso)     | <http://id.nlm.nih.gov/mesh/D020734>                                |
| disease:1238 | pref label (skos:prefLabel) | Parkinson disease 2                                                 |
| disease:1238 | comment (rdfs:comment)      | A neurodegenerative disorder cha...aggregated proteins) are absent. |
| disease:1238 | Mnemonic (up:mnemonic)      | PARK2                                                               |
| disease:1238 | alt label (skos:altLabel)   | Autosomal recessive early-onset Parkinson disease type 2            |
| disease:1238 | see also (rdfs:seeAlso)     | 523 (keywords:523)                                                  |
| disease:1238 | see also (rdfs:seeAlso)     | 907 (keywords:907)                                                  |
| disease:1238 | see also (rdfs:seeAlso)     | 908 (keywords:908)                                                  |
| disease:1238 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/medgen/C1868675>                           |
| ...          | ...                         | ...                                                                 |

[Tool]
Got 12 rows and 3 columns, showing the first 10 rows below:
| subject      | property                    | object                                                              |
| ------------ | --------------------------- | ------------------------------------------------------------------- |
| disease:1278 | type (rdf:type)             | Disease (up:Disease)                                                |
| disease:1278 | see also (rdfs:seeAlso)     | <http://id.nlm.nih.gov/mesh/D010661>                                |
| disease:1278 | pref label (skos:prefLabel) | Hyperphenylalaninemia, BH4-deficient, C                             |
| disease:1278 | comment (rdfs:comment)      | Rare autosomal recessive disorde... HPABH4C is lethal if untreated. |
| disease:1278 | Mnemonic (up:mnemonic)      | HPABH4C                                                             |
| disease:1278 | alt label (skos:altLabel)   | DHPR deficiency                                                     |
| disease:1278 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/medgen/C0268465>                           |
| disease:1278 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/mim/261630>                                |
| disease:1278 | alt label (skos:altLabel)   | Dihydropteridine reductase deficiency                               |
| disease:1278 | alt label (skos:altLabel)   | Hyperphenylalaninemia tetrahydro...deficient due to DHPR deficiency |
| ...          | ...                         | ...                                                                 |

[Tool]
Got 19 rows and 3 columns, showing the first 10 rows below:
| subject      | property                    | object                                                              |
| ------------ | --------------------------- | ------------------------------------------------------------------- |
| disease:1302 | type (rdf:type)             | Disease (up:Disease)                                                |
| disease:1302 | see also (rdfs:seeAlso)     | <http://id.nlm.nih.gov/mesh/D008661>                                |
| disease:1302 | pref label (skos:prefLabel) | Butyrylcholinesterase deficiency                                    |
| disease:1302 | comment (rdfs:comment)      | An autosomal recessive metabolic...extent of the enzyme deficiency. |
| disease:1302 | Mnemonic (up:mnemonic)      | BCHED                                                               |
| disease:1302 | alt label (skos:altLabel)   | Acholinesterasemia                                                  |
| disease:1302 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/medgen/C0268379>                           |
| disease:1302 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/medgen/C1283400>                           |
| disease:1302 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/medgen/C1622434>                           |
| disease:1302 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/medgen/C1867467>                           |
| ...          | ...                         | ...                                                                 |

[Tool]
Got 23 rows and 3 columns, showing the first 10 rows below:
| subject      | property                    | object                                                              |
| ------------ | --------------------------- | ------------------------------------------------------------------- |
| disease:1440 | type (rdf:type)             | Disease (up:Disease)                                                |
| disease:1440 | see also (rdfs:seeAlso)     | <http://id.nlm.nih.gov/mesh/D006223>                                |
| disease:1440 | pref label (skos:prefLabel) | Cowden syndrome 1                                                   |
| disease:1440 | comment (rdfs:comment)      | An autosomal dominant hamartomat...tinal tract, breast and thyroid. |
| disease:1440 | Mnemonic (up:mnemonic)      | CWS1                                                                |
| disease:1440 | alt label (skos:altLabel)   | Bannayan-Riley-Ruvalcaba syndrome                                   |
| disease:1440 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/medgen/C0018553>                           |
| disease:1440 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/mim/158350>                                |
| disease:1440 | alt label (skos:altLabel)   | Bannayan-Ruvalcaba-Riley syndrome                                   |
| disease:1440 | alt label (skos:altLabel)   | Bannayan-Zonana syndrome                                            |
| ...          | ...                         | ...                                                                 |

[Tool]
Got 11 rows and 3 columns, showing the first 10 rows below:
| subject      | property                    | object                                                              |
| ------------ | --------------------------- | ------------------------------------------------------------------- |
| disease:1541 | type (rdf:type)             | Disease (up:Disease)                                                |
| disease:1541 | see also (rdfs:seeAlso)     | <http://id.nlm.nih.gov/mesh/D005168>                                |
| disease:1541 | pref label (skos:prefLabel) | Factor VII deficiency                                               |
| disease:1541 | comment (rdfs:comment)      | A hemorrhagic disease with varia...pite very low factor VII levels. |
| disease:1541 | Mnemonic (up:mnemonic)      | FA7D                                                                |
| disease:1541 | alt label (skos:altLabel)   | Congenital proconvertin deficiency                                  |
| disease:1541 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/medgen/C0015503>                           |
| disease:1541 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/mim/227500>                                |
| disease:1541 | alt label (skos:altLabel)   | F7 deficiency                                                       |
| disease:1541 | alt label (skos:altLabel)   | Factor 7 deficiency                                                 |
| ...          | ...                         | ...                                                                 |

[Tool]
Got 14 rows and 3 columns, showing the first 10 rows below:
| subject      | property                    | object                                                              |
| ------------ | --------------------------- | ------------------------------------------------------------------- |
| disease:1542 | type (rdf:type)             | Disease (up:Disease)                                                |
| disease:1542 | see also (rdfs:seeAlso)     | <http://id.nlm.nih.gov/mesh/D005173>                                |
| disease:1542 | pref label (skos:prefLabel) | Factor XI deficiency                                                |
| disease:1542 | comment (rdfs:comment)      | A hemorrhagic disease characteri...emorrhages are usually moderate. |
| disease:1542 | Mnemonic (up:mnemonic)      | FA11D                                                               |
| disease:1542 | alt label (skos:altLabel)   | F11 deficiency                                                      |
| disease:1542 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/medgen/C0015523>                           |
| disease:1542 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/mim/612416>                                |
| disease:1542 | alt label (skos:altLabel)   | Factor 11 deficiency                                                |
| disease:1542 | alt label (skos:altLabel)   | Hemophilia C                                                        |
| ...          | ...                         | ...                                                                 |

[Tool]
Got 7 rows and 3 columns:
| subject      | property                    | object                                                              |
| ------------ | --------------------------- | ------------------------------------------------------------------- |
| disease:1544 | type (rdf:type)             | Disease (up:Disease)                                                |
| disease:1544 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/medgen/C0002986>                           |
| disease:1544 | pref label (skos:prefLabel) | Fabry disease                                                       |
| disease:1544 | comment (rdfs:comment)      | Rare X-linked sphingolipidosis d...ikely to show corneal opacities. |
| disease:1544 | Mnemonic (up:mnemonic)      | FD                                                                  |
| disease:1544 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/medgen/C1970820>                           |
| disease:1544 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/mim/301500>                                |

[Tool]
Got 11 rows and 3 columns, showing the first 10 rows below:
| subject     | property                    | object                                                              |
| ----------- | --------------------------- | ------------------------------------------------------------------- |
| disease:133 | type (rdf:type)             | Disease (up:Disease)                                                |
| disease:133 | see also (rdfs:seeAlso)     | <http://id.nlm.nih.gov/mesh/D000592>                                |
| disease:133 | pref label (skos:prefLabel) | Argininosuccinic aciduria                                           |
| disease:133 | comment (rdfs:comment)      | An autosomal recessive disorder ...s, and episodic unconsciousness. |
| disease:133 | Mnemonic (up:mnemonic)      | ARGINSA                                                             |
| disease:133 | alt label (skos:altLabel)   | Argininosuccinase deficiency                                        |
| disease:133 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/medgen/C0268547>                           |
| disease:133 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/mim/207900>                                |
| disease:133 | alt label (skos:altLabel)   | Argininosuccinic acid lyase deficiency                              |
| disease:133 | alt label (skos:altLabel)   | ASAuria                                                             |
| ...         | ...                         | ...                                                                 |

[Tool]
Got 17 rows and 3 columns, showing the first 10 rows below:
| subject      | property                    | object                                                              |
| ------------ | --------------------------- | ------------------------------------------------------------------- |
| disease:1911 | type (rdf:type)             | Disease (up:Disease)                                                |
| disease:1911 | see also (rdfs:seeAlso)     | <http://id.nlm.nih.gov/mesh/D006951>                                |
| disease:1911 | pref label (skos:prefLabel) | Hyperlipoproteinemia 1                                              |
| disease:1911 | comment (rdfs:comment)      | An autosomal recessive metabolic...licated with acute pancreatitis. |
| disease:1911 | Mnemonic (up:mnemonic)      | HLPP1                                                               |
| disease:1911 | alt label (skos:altLabel)   | Chylomicronemia, familial                                           |
| disease:1911 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/medgen/C0023817>                           |
| disease:1911 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/medgen/C1706413>                           |
| disease:1911 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/mim/238600>                                |
| disease:1911 | alt label (skos:altLabel)   | Hyperchylomicronemia, familial                                      |
| ...          | ...                         | ...                                                                 |

[Tool]
Got 11 rows and 3 columns, showing the first 10 rows below:
| subject      | property                    | object                                                              |
| ------------ | --------------------------- | ------------------------------------------------------------------- |
| disease:1729 | type (rdf:type)             | Disease (up:Disease)                                                |
| disease:1729 | see also (rdfs:seeAlso)     | <http://id.nlm.nih.gov/mesh/D000746>                                |
| disease:1729 | pref label (skos:prefLabel) | Anemia, congenital, non-spherocytic hemolytic, 4                    |
| disease:1729 | comment (rdfs:comment)      | An autosomal recessive form of a... phosphate isomerase deficiency. |
| disease:1729 | Mnemonic (up:mnemonic)      | CNSHA4                                                              |
| disease:1729 | alt label (skos:altLabel)   | Anemia, congenital, nonspherocytic hemolytic, 4                     |
| disease:1729 | see also (rdfs:seeAlso)     | <http://id.nlm.nih.gov/mesh/D008661>                                |
| disease:1729 | see also (rdfs:seeAlso)     | 360 (keywords:360)                                                  |
| disease:1729 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/medgen/C3150730>                           |
| disease:1729 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/mim/613470>                                |
| ...          | ...                         | ...                                                                 |

[Tool]
Got 12 rows and 3 columns, showing the first 10 rows below:
| subject     | property                    | object                                                              |
| ----------- | --------------------------- | ------------------------------------------------------------------- |
| disease:883 | type (rdf:type)             | Disease (up:Disease)                                                |
| disease:883 | see also (rdfs:seeAlso)     | <http://id.nlm.nih.gov/mesh/D020163>                                |
| disease:883 | pref label (skos:prefLabel) | Ornithine carbamoyltransferase deficiency                           |
| disease:883 | comment (rdfs:comment)      | An X-linked disorder of the urea...rentiate severe from mild forms. |
| disease:883 | Mnemonic (up:mnemonic)      | OTCD                                                                |
| disease:883 | alt label (skos:altLabel)   | Hyperammonemia due to ornithine carbamoyltransferase deficiency     |
| disease:883 | see also (rdfs:seeAlso)     | <http://id.nlm.nih.gov/mesh/D022124>                                |
| disease:883 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/medgen/C0268542>                           |
| disease:883 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/medgen/C1839530>                           |
| disease:883 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/mim/311250>                                |
| ...         | ...                         | ...                                                                 |

[Tool]
Got 10 rows and 3 columns:
| subject     | property                    | object                                                              |
| ----------- | --------------------------- | ------------------------------------------------------------------- |
| disease:185 | type (rdf:type)             | Disease (up:Disease)                                                |
| disease:185 | see also (rdfs:seeAlso)     | <http://id.nlm.nih.gov/mesh/D002780>                                |
| disease:185 | pref label (skos:prefLabel) | Cholestasis, benign recurrent intrahepatic, 1                       |
| disease:185 | comment (rdfs:comment)      | A disorder characterized by inte...th clinically and biochemically. |
| disease:185 | Mnemonic (up:mnemonic)      | BRIC1                                                               |
| disease:185 | alt label (skos:altLabel)   | Recurrent familial intrahepatic cholestasis                         |
| disease:185 | see also (rdfs:seeAlso)     | 988 (keywords:988)                                                  |
| disease:185 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/medgen/C1855731>                           |
| disease:185 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/mim/243300>                                |
| disease:185 | alt label (skos:altLabel)   | Summerskill syndrome                                                |

[Tool]
Got 13 rows and 3 columns, showing the first 10 rows below:
| subject     | property                    | object                                                              |
| ----------- | --------------------------- | ------------------------------------------------------------------- |
| disease:811 | type (rdf:type)             | Disease (up:Disease)                                                |
| disease:811 | see also (rdfs:seeAlso)     | <http://id.nlm.nih.gov/mesh/D009472>                                |
| disease:811 | pref label (skos:prefLabel) | Ceroid lipofuscinosis, neuronal, 2                                  |
| disease:811 | comment (rdfs:comment)      | A form of neuronal ceroid lipofu...onsists of curvilinear profiles. |
| disease:811 | Mnemonic (up:mnemonic)      | CLN2                                                                |
| disease:811 | alt label (skos:altLabel)   | Jansky-Bielschowsky disease                                         |
| disease:811 | see also (rdfs:seeAlso)     | 525 (keywords:525)                                                  |
| disease:811 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/medgen/C0022340>                           |
| disease:811 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/medgen/C1876161>                           |
| disease:811 | see also (rdfs:seeAlso)     | <http://purl.uniprot.org/mim/204500>                                |
| ...         | ...                         | ...                                                                 |

[Assistant]
Here are some examples of human genetic diseases that are related to a natural variant located on the active site of an enzyme, based on UniProt data:

- Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1 (SCAN1) — disease:1064
- Amyotrophic lateral sclerosis 9 (ALS9) — disease:113
- Parkinson disease 2 (PARK2) — disease:1238
- Hyperphenylalaninemia, BH4-deficient, C (HPABH4C) — disease:1278
- Butyrylcholinesterase deficiency (BCHED) — disease:1302
- Cowden syndrome 1 (CWS1) — disease:1440
- Factor VII deficiency (FA7D) — disease:1541
- Factor XI deficiency (FA11D) — disease:1542
- Fabry disease (FD) — disease:1544
- Argininosuccinic aciduria (ARGINSA) — disease:133
- Hyperlipoproteinemia 1 (HLPP1) — disease:1911
- Anemia, congenital, non-spherocytic hemolytic, 4 (CNSHA4) — disease:1729
- Ornithine carbamoyltransferase deficiency (OTCD) — disease:883
- Cholestasis, benign recurrent intrahepatic, 1 (BRIC1) — disease:185
- Ceroid lipofuscinosis, neuronal, 2 (CLN2) — disease:811

These diseases are linked to natural variants that are annotated at the same position as an active site in a human enzyme.

Here is a SPARQL query that retrieves such diseases:

```sparql
SELECT DISTINCT ?disease ?diseaseLabel WHERE {
  ?protein up:organism taxon:9606 .
  ?protein up:enzyme ?enzyme .
  ?protein up:annotation ?variant .
  ?variant a up:Natural_Variant_Annotation .
  ?variant skos:related ?disease .
  ?protein up:annotation ?activeSite .
  ?activeSite a up:Active_Site_Annotation .
  ?variant up:range ?vrange .
  ?activeSite up:range ?arange .
  FILTER(?vrange = ?arange)
  OPTIONAL { ?disease skos:prefLabel ?diseaseLabel }
} LIMIT 20
```

This query efficiently finds human genetic diseases related to a natural variant located on the active site of an enzyme.

[User]
Feedback (status=retry):
The SPARQL query is conceptually on the right track, but it fails to execute due to excessive memory usage. This is likely because it joins all natural variants and active sites for all human proteins, then filters for those with matching ranges, which is computationally expensive. To improve, consider:

1. Restricting the query to only proteins that are enzymes (if possible, by filtering for those with an EC number or similar property).
2. Using more specific joins or limiting the number of annotations considered at once (e.g., by limiting to variants already known to be disease-related before joining with active sites).
3. If possible, use a property path or a more efficient way to match variants and active sites at the same position, perhaps by matching on a position integer rather than a range object.

Additionally, the query should always return the actual IRIs of the diseases, which it does. However, the query needs to be reworked for efficiency and feasibility on the endpoint.

[Assistant]
Thank you for the detailed feedback. To address the memory issue and improve efficiency, I will:

1. Restrict to proteins that are enzymes by requiring an EC number (up:enzyme).
2. Only consider natural variants that are already linked to a disease (skos:related).
3. Instead of joining on the entire range object, I will attempt to extract and match the position integer if possible, or at least limit the join to annotations within the same protein.
4. Limit the number of results to avoid large intermediate sets.

First, I will inspect how the up:range property is structured for both natural variants and active site annotations, to see if a position integer can be extracted for a more efficient join.

[Tool]
Got 6 rows and 3 columns:
| subject               | property                       | object                                                              |
| --------------------- | ------------------------------ | ------------------------------------------------------------------- |
| annotation:VAR_009612 | type (rdf:type)                | Sequence Variant (up:Natural_Variant_Annotation)                    |
| annotation:VAR_009612 | see also (rdfs:seeAlso)        | <http://purl.uniprot.org/dbsnp/rs121908202>                         |
| annotation:VAR_009612 | comment (rdfs:comment)         | In CLN2; displays no residual en...ely transported to the lysosome. |
| annotation:VAR_009612 | range (up:range)               | range:22290623494566702tt475tt475                                   |
| annotation:VAR_009612 | substitution (up:substitution) | L                                                                   |
| annotation:VAR_009612 | related (skos:related)         | disease:811                                                         |

[Tool]
Got 3 rows and 3 columns:
| subject                                                      | property               | object                                  |
| ------------------------------------------------------------ | ---------------------- | --------------------------------------- |
| <http://purl.uniprot.org/uniprot/O14773#SIP8DF7F8B8F67305BC> | type (rdf:type)        | Active Site (up:Active_Site_Annotation) |
| <http://purl.uniprot.org/uniprot/O14773#SIP8DF7F8B8F67305BC> | comment (rdfs:comment) | Charge relay system                     |
| <http://purl.uniprot.org/uniprot/O14773#SIP8DF7F8B8F67305BC> | range (up:range)       | range:22290623494566702tt475tt475       |

[Tool]
Got 3 rows and 3 columns:
| subject                           | property            | object                          |
| --------------------------------- | ------------------- | ------------------------------- |
| range:22290623494566702tt475tt475 | type (rdf:type)     | faldo:Region                    |
| range:22290623494566702tt475tt475 | begin (faldo:begin) | position:22290623494566702tt475 |
| range:22290623494566702tt475tt475 | end (faldo:end)     | position:22290623494566702tt475 |

[Tool]
Got 4 rows and 3 columns:
| subject                         | property                    | object              |
| ------------------------------- | --------------------------- | ------------------- |
| position:22290623494566702tt475 | type (rdf:type)             | faldo:ExactPosition |
| position:22290623494566702tt475 | reference (faldo:reference) | isoform:O14773-1    |
| position:22290623494566702tt475 | position (faldo:position)   | 475 (xsd:int)       |
| position:22290623494566702tt475 | type (rdf:type)             | faldo:Position      |

[Tool]
Got 5 rows and 3 columns:
| subject               | property                       | object                                           |
| --------------------- | ------------------------------ | ------------------------------------------------ |
| annotation:VAR_043057 | type (rdf:type)                | Sequence Variant (up:Natural_Variant_Annotation) |
| annotation:VAR_043057 | comment (rdfs:comment)         | In BRIC1.                                        |
| annotation:VAR_043057 | range (up:range)               | range:22293917700599854tt454tt454                |
| annotation:VAR_043057 | substitution (up:substitution) | G                                                |
| annotation:VAR_043057 | related (skos:related)         | disease:185                                      |

[Tool]
Got 3 rows and 3 columns:
| subject                           | property            | object                          |
| --------------------------------- | ------------------- | ------------------------------- |
| range:22293917700599854tt454tt454 | type (rdf:type)     | faldo:Region                    |
| range:22293917700599854tt454tt454 | begin (faldo:begin) | position:22293917700599854tt454 |
| range:22293917700599854tt454tt454 | end (faldo:end)     | position:22293917700599854tt454 |

[Tool]
Got 4 rows and 3 columns:
| subject                         | property                    | object              |
| ------------------------------- | --------------------------- | ------------------- |
| position:22293917700599854tt454 | type (rdf:type)             | faldo:ExactPosition |
| position:22293917700599854tt454 | reference (faldo:reference) | isoform:O43520-1    |
| position:22293917700599854tt454 | position (faldo:position)   | 454 (xsd:int)       |
| position:22293917700599854tt454 | type (rdf:type)             | faldo:Position      |

[Tool]
SPARQL execution failed:
Tried to allocate 48.5 GB, but only 20 GB were available. Clear the cache or allow more memory for QLever during startup

[Tool]
Got 10 rows and 1 column:
| disease      |
| ------------ |
| disease:1064 |
| disease:113  |
| disease:1238 |
| disease:1278 |
| disease:1302 |
| disease:133  |
| disease:1440 |
| disease:1541 |
| disease:1542 |
| disease:1544 |

[Tool] Stopped generation process