HGD

Summary

HGD (homogentisate 1,2-dioxygenase, HGNC:4892) is a protein-coding gene on chromosome 3q13.33, encoding Homogentisate 1,2-dioxygenase (Q93099). Catalyzes the conversion of homogentisate to maleylacetoacetate.

This gene encodes the enzyme homogentisate 1,2 dioxygenase. This enzyme is involved in the catabolism of the amino acids tyrosine and phenylalanine. Mutations in this gene are the cause of the autosomal recessive metabolism disorder alkaptonuria.

Source: NCBI Gene 3081 — RefSeq curated summary.

At a glance

• Gene–disease (curated): alkaptonuria (Definitive, ClinGen)
• Clinical variants (ClinVar): 639 total — 185 pathogenic, 68 likely-pathogenic
• Phenotypes (HPO): 65
• MANE Select transcript: NM_000187

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4892
Approved symbol	HGD
Name	homogentisate 1,2-dioxygenase
Location	3q13.33
Locus type	gene with protein product
Status	Approved
Aliases	HGO
Ensembl gene	ENSG00000113924
Ensembl biotype	protein_coding
OMIM	607474
Entrez	3081

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 20 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000283871, ENST00000466528, ENST00000470321, ENST00000475447, ENST00000476082, ENST00000480862, ENST00000485313, ENST00000488183, ENST00000492108, ENST00000494453, ENST00000898830, ENST00000898831, ENST00000898832, ENST00000898833, ENST00000898834, ENST00000898835, ENST00000898836, ENST00000898837, ENST00000898838, ENST00000898839, ENST00000898840, ENST00000898841, ENST00000898842, ENST00000898843, ENST00000898844, ENST00000955340

RefSeq mRNA: 1 — MANE Select: NM_000187 NM_000187

CCDS: CCDS3000

Canonical transcript exons

ENST00000283871 — 14 exons

Exon	Start	End
ENSE00001686509	120647877	120647911
ENSE00001740085	120650774	120650865
ENSE00001743017	120628172	120628529
ENSE00001751280	120644319	120644443
ENSE00001950843	120682097	120682239
ENSE00002211361	120646267	120646366
ENSE00003466987	120670427	120670532
ENSE00003520096	120633147	120633328
ENSE00003547022	120652592	120652651
ENSE00003569562	120641589	120641693
ENSE00003578622	120675792	120675863
ENSE00003586499	120638455	120638581
ENSE00003632972	120674901	120674989
ENSE00003788828	120646973	120647052

Expression profiles

Bgee: expression breadth ubiquitous, 191 present calls, max score 99.19.

FANTOM5 (CAGE): breadth broad, TPM avg 2.8460 / max 509.1966, expressed in 189 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
44085	2.4653	133
44083	0.2216	56
44082	0.1263	45
44084	0.0196	10
44086	0.0070	3
44087	0.0062	4

Top tissues by expression

284 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.19	gold quality
liver	UBERON:0002107	98.30	gold quality
gall bladder	UBERON:0002110	97.00	gold quality
adult mammalian kidney	UBERON:0000082	96.11	gold quality
right lobe of thyroid gland	UBERON:0001119	96.05	gold quality
nephron tubule	UBERON:0001231	95.62	gold quality
left lobe of thyroid gland	UBERON:0001120	95.50	gold quality
metanephros cortex	UBERON:0010533	94.92	gold quality
thyroid gland	UBERON:0002046	94.79	gold quality
kidney epithelium	UBERON:0004819	92.81	gold quality
kidney	UBERON:0002113	92.77	gold quality
body of pancreas	UBERON:0001150	92.42	gold quality
islet of Langerhans	UBERON:0000006	91.85	gold quality
cortex of kidney	UBERON:0001225	91.41	gold quality
pancreas	UBERON:0001264	90.83	gold quality
mucosa of transverse colon	UBERON:0004991	90.77	gold quality
rectum	UBERON:0001052	90.45	gold quality
renal glomerulus	UBERON:0000074	90.42	gold quality
metanephric glomerulus	UBERON:0004736	90.30	gold quality
duodenum	UBERON:0002114	87.90	gold quality
metanephros	UBERON:0000081	87.60	gold quality
prostate gland	UBERON:0002367	87.29	gold quality
endometrium	UBERON:0001295	86.75	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.61	gold quality
monocyte	CL:0000576	85.98	gold quality
mononuclear cell	CL:0000842	85.42	gold quality
small intestine Peyer’s patch	UBERON:0003454	85.09	gold quality
leukocyte	CL:0000738	84.68	gold quality
body of stomach	UBERON:0001161	83.82	gold quality
small intestine	UBERON:0002108	83.32	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-81608	yes	8.47
E-CURD-10	no	771.54
E-ENAD-27	no	3.74
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

17 targeting HGD, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-4762-5P	99.57	68.54	1424
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-1226-3P	97.51	66.32	1063
HSA-MIR-148B-5P	97.29	66.30	992
HSA-MIR-6874-3P	97.29	66.34	975
HSA-MIR-6869-5P	97.17	67.06	634
HSA-MIR-10525-3P	96.32	68.04	699
HSA-MIR-5186	94.63	66.76	627
HSA-MIR-6854-3P	90.99	65.18	155

Literature-anchored findings (GeneRIF, showing 19)

• Turkish mutation shares an homogentisate 1,2-dioxygenase haplotype with the mutation found in Finland, Slovakia and India, suggesting that R58fs is an old alkaptonuria mutation that probably originated in central Asia (PMID:12872836)
• Four different mutations of the HGD gene were found in alkaptonuria and ochronotic arthropathy diagnoses. (PMID:16085442)
• A single nucleotide deletion located in exon 3 resulted in a frameshift mutation in HGD gene in family with alkaptonuria. (PMID:18945288)
• A comprehensive mutation analysis of 93 patients enrolled in this study, as well as an extensive update of all previously published HGD mutations associated with alkaptonuria, is reported. (PMID:19862842)
• Familiar ochronotic arthropathy is caused by a gene mutation of the homogentisic acid 1,2-dioxygenase (HGD) gene traced three hundred years in a Hungarian family. (PMID:20462779)
• Report mutations of the HGD gene in Jordanian alkaptonuria patients. (PMID:21437689)
• An update on molecular genetics of Alkaptonuria (AKU).(review) (PMID:21720873)
• The observed increase of HGD expression in Alkaptonuria cells is probably due to a compensatory mechanism to overcome the almost null catalytic activity of the deficient enzyme (PMID:22105303)
• study described two novel HGD mutations in a Chinese alkaptonuria family, the splicing mutation of IVS7 1G>C, a donor splice site of exon 7, and a missense mutation of F329C in exon 12 (PMID:23353776)
• A novel alkaptonuria mutation, c.87 + 1G > A, shows a significant founder effect and high prevalence in a nomadic Indian population. (PMID:24575791)
• Twelve novel HGD gene variants have been identified in 99 alkaptonuria patients affecting the bones. (PMID:25804398)
• Homogentisate 1,2-dioxygenase (HGD) gene variants, their analysis and genotype-phenotype correlations in the largest cohort of patients with AKU. (PMID:30737480)
• Presentation of 14 alkaptonuria patients from Turkey. (PMID:31927521)
• Screening and molecular characterization of lethal mutations of human homogentisate 1, 2 dioxigenase. (PMID:32107984)
• Founder effects of the homogentisate 1,2-dioxygenase (HGD) gene in a gypsy population and mutation spectrum in the gene among alkaptonuria patients from India. (PMID:32212000)
• Alkaptonuria in Russia: mutational spectrum and novel variants. (PMID:33621656)
• A novel mutation in the homogentisate 1,2 dioxygenase gene identified in Chinese Hani pediatric patients with Alkaptonuria. (PMID:35550814)
• Structure-Function Relationship of Homogentisate 1,2-dioxygenase: Understanding the Genotype-Phenotype Correlations in the Rare Genetic Disease Alkaptonuria. (PMID:36880186)
• Homogentisate 1,2-dioxygenase (HGD) gene variants in young Egyptian patients with alkaptonuria. (PMID:37658095)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hgd	ENSDARG00000058005
mus_musculus	Hgd	ENSMUSG00000022821
rattus_norvegicus	Hgd	ENSRNOG00000002701
drosophila_melanogaster	hgo	FBGN0040211
caenorhabditis_elegans	hgo-1	WBGENE00001843

Protein

Protein identifiers

Homogentisate 1,2-dioxygenase — Q93099 (reviewed: Q93099)

Alternative names: Homogentisate oxygenase, Homogentisic acid oxidase, Homogentisicase

All UniProt accessions (5): C9JTX9, Q93099, H7C4R8, H7C576, H7C5G7

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the conversion of homogentisate to maleylacetoacetate.

Subunit / interactions. Homohexamer arranged as a dimer of trimers.

Tissue specificity. Highest expression in the prostate, small intestine, colon, kidney and liver.

Disease relevance. Alkaptonuria (AKU) [MIM:203500] An autosomal recessive error of metabolism characterized by an increase in the level of homogentisic acid. The clinical manifestations are urine that turns dark on standing and alkalinization, black ochronotic pigmentation of cartilage and collagenous tissues, and spine arthritis. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Amino-acid degradation; L-phenylalanine degradation; acetoacetate and fumarate from L-phenylalanine: step 4/6.

Similarity. Belongs to the homogentisate dioxygenase family.

RefSeq proteins (1): NP_000178* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005708	Homogentis_dOase	Family
IPR011051	RmlC_Cupin_sf	Homologous_superfamily
IPR014710	RmlC-like_jellyroll	Homologous_superfamily
IPR046451	HgmA_C	Domain
IPR046452	HgmA_N	Domain

Pfam: PF04209, PF20510

Enzyme classification (BRENDA):

• EC 1.13.11.5 — homogentisate 1,2-dioxygenase (BRENDA: 35 organisms, 39 substrates, 40 inhibitors, 13 Km, 9 kcat entries)

Substrate kinetics (BRENDA)

3 substrates with measured Km, best-characterized 3. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
HOMOGENTISATE	0.009–0.6	13
3-CHLOROHOMOGENTISATE	—	0
3-METHYLHOMOGENTISATE	—	0

Catalyzed reactions (Rhea), 1 shown:

• homogentisate + O2 = 4-maleylacetoacetate + H(+) (RHEA:15449)

UniProt features (116 total): sequence variant 70, strand 27, helix 10, binding site 3, modified residue 2, turn 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1EYB	X-RAY DIFFRACTION	1.9
1EY2	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q93099-F1	96.85	0.96

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (3): 335; 341; 371

Post-translational modifications (2): 98, 414

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8963684	Tyrosine catabolism

MSigDB gene sets: 250 (showing top): GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, DARWICHE_PAPILLOMA_PROGRESSION_RISK, MODULE_503, CAIRO_HEPATOBLASTOMA_CLASSES_DN, BOYAULT_LIVER_CANCER_SUBCLASS_G12_DN, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, GOBP_AROMATIC_AMINO_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, DELYS_THYROID_CANCER_DN, HSIAO_LIVER_SPECIFIC_GENES, CAIRO_HEPATOBLASTOMA_DN, CORRE_MULTIPLE_MYELOMA_UP, MODULE_373, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_CATABOLIC_PROCESS

GO Biological Process (4): L-phenylalanine catabolic process (GO:0006559), L-tyrosine catabolic process (GO:0006572), amino acid metabolic process (GO:0006520), obsolete tyrosine metabolic process (GO:0006570)

GO Molecular Function (6): homogentisate 1,2-dioxygenase activity (GO:0004411), identical protein binding (GO:0042802), metal ion binding (GO:0046872), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), dioxygenase activity (GO:0051213)

GO Cellular Component (2): cytosol (GO:0005829), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Phenylalanine and tyrosine metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
aromatic amino acid catabolic process	2
L-amino acid catabolic process	2
proteinogenic amino acid catabolic process	2
primary metabolic process	1
oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen	1
protein binding	1
cation binding	1
binding	1
catalytic activity	1
oxidoreductase activity	1
cytoplasm	1
cellular anatomical structure	1
extracellular vesicle	1

Protein interactions and networks

STRING

1510 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HGD	HPD	P32754	757
HGD	FAH	P16930	736
HGD	GSTZ1	O43708	725
HGD	TAT	P17735	710
HGD	PAH	P00439	585
HGD	AASS	Q9UDR5	558
HGD	HPDL	Q96IR7	518
HGD	KMO	O15229	491
HGD	SDS	P20132	462
HGD	IVD	P26440	462
HGD	KYNU	Q16719	459
HGD	OAT	P04181	442
HGD	HAL	P42357	436
HGD	UROD	P06132	434
HGD	ALDH6A1	Q02252	426

IntAct

14 interactions, top by confidence:

A	B	Type	Score
HGD	HGD	psi-mi:“MI:0915”(physical association)	0.670
HGD	NTAQ1	psi-mi:“MI:0915”(physical association)	0.560
TERF1	HGD	psi-mi:“MI:0915”(physical association)	0.510
Dlg4	HGD	psi-mi:“MI:0407”(direct interaction)	0.440
CLDN7	HGD	psi-mi:“MI:0915”(physical association)	0.370
PCDHGC3	HGD	psi-mi:“MI:0915”(physical association)	0.370
HGD	GIT2	psi-mi:“MI:0915”(physical association)	0.370
HGD	TERF1	psi-mi:“MI:0915”(physical association)	0.000
NTAQ1	HGD	psi-mi:“MI:0915”(physical association)	0.000
HGD	HGD	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (9): HGD (Two-hybrid), HGD (Two-hybrid), WDYHV1 (Two-hybrid), HGD (Proximity Label-MS), HGD (Affinity Capture-MS), HGD (Two-hybrid), HGD (Two-hybrid), PCDHGC3 (Two-hybrid), HGD (Two-hybrid)

ESM2 similar proteins: A0A1D8PCB9, A0A1D8PI71, A0A1U8QNM5, A0A345BJQ0, C4R4B3, C4R7Z3, G9N4A5, I1RJD6, I1RT23, O09173, O55242, P25618, P29704, P32352, P32360, P33281, P36596, P78589, P87113, Q00667, Q00912, Q4WHT9, Q4WJU9, Q54DR1, Q54QI4, Q55BU8, Q58DH7, Q5APD4, Q5PXE2, Q5PXE3, Q5RF05, Q5ZL84, Q60492, Q645J3, Q66IM1, Q6DCU6, Q752X9, Q7S4Z6, Q7ZWG9, Q92206

Diamond homologs: A0K4Z6, A1V1U3, A2S9M1, A3MMH2, A3NYN0, A4JBW6, A5IBD8, A5W8Z1, A6UDD3, A6V6F5, A9AFM6, A9I714, B0KGU6, B0T816, B1J390, B1JWJ3, B1YTZ1, B2SM18, B2UJ73, B3PWZ9, B3QB98, B4ECX5, B5ZZA8, B7VA96, B8H072, B9JHZ9, C3M930, O09173, Q00667, Q02LF6, Q07T66, Q0BHW3, Q0K0L8, Q13CD3, Q1BYQ6, Q1D8L9, Q1I500, Q1MI52, Q1QPR8, Q21AX5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

639 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	185
Likely pathogenic	68
Uncertain significance	134
Likely benign	174
Benign	13

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069590	NM_000187.4(HGD):c.1006+2T>A	Pathogenic
1071828	NM_000187.4(HGD):c.1288del (p.Leu430fs)	Pathogenic
1073765	NM_000187.4(HGD):c.1188+1G>A	Pathogenic
1075699	NM_000187.4(HGD):c.186T>G (p.Tyr62Ter)	Pathogenic
1076110	NM_000187.4(HGD):c.1185del (p.Met396fs)	Pathogenic
1264347	NM_000187.4(HGD):c.1031del (p.Gly344fs)	Pathogenic
1368315	NM_000187.4(HGD):c.1245del (p.Ser416fs)	Pathogenic
1387389	NM_000187.4(HGD):c.359G>T (p.Cys120Phe)	Pathogenic
1450820	NM_000187.4(HGD):c.502G>T (p.Glu168Ter)	Pathogenic
1454693	NM_000187.4(HGD):c.1111del (p.His371fs)	Pathogenic
1457863	NM_000187.4(HGD):c.1007-2A>T	Pathogenic
1458490	NM_000187.4(HGD):c.1269C>A (p.Tyr423Ter)	Pathogenic
156275	NM_000187.4(HGD):c.16-272_87+305del	Pathogenic
188865	NM_000187.4(HGD):c.365C>T (p.Ala122Val)	Pathogenic
189061	NM_000187.4(HGD):c.652del	Pathogenic
189127	NM_000187.4(HGD):c.342+1G>T	Pathogenic
189173	NM_000187.4(HGD):c.674G>A (p.Arg225His)	Pathogenic
1986548	NM_000187.4(HGD):c.699G>A (p.Trp233Ter)	Pathogenic
2003221	NM_000187.4(HGD):c.1112dup (p.His371fs)	Pathogenic
2004589	NM_000187.4(HGD):c.133del (p.Ser45fs)	Pathogenic
2026406	NM_000187.4(HGD):c.1157_1160del (p.Leu386fs)	Pathogenic
2064427	NM_000187.4(HGD):c.1188+2T>A	Pathogenic
2069488	NM_000187.4(HGD):c.237_240del (p.Gln80fs)	Pathogenic
2088945	NM_000187.4(HGD):c.378del (p.Lys126fs)	Pathogenic
2110947	NM_000187.4(HGD):c.434+1del	Pathogenic
2112733	NM_000187.4(HGD):c.448del (p.Ser150fs)	Pathogenic
2148805	NM_000187.4(HGD):c.650-13T>G	Pathogenic
2180413	NM_000187.4(HGD):c.413_434+35del	Pathogenic
2191885	NM_000187.4(HGD):c.673del (p.Arg225fs)	Pathogenic
2200215	NM_000187.4(HGD):c.588del (p.Arg197fs)	Pathogenic

SpliceAI

2036 predictions. Top by Δscore:

Variant	Effect	Δscore
3:120641584:CT:C	donor_loss	1.0000
3:120641585:TT:T	donor_loss	1.0000
3:120641586:TA:T	donor_loss	1.0000
3:120641587:A:AC	donor_gain	1.0000
3:120641587:ACTG:A	donor_gain	1.0000
3:120641588:C:CA	donor_gain	1.0000
3:120641588:CT:C	donor_gain	1.0000
3:120641588:CTG:C	donor_gain	1.0000
3:120641588:CTGC:C	donor_gain	1.0000
3:120641588:CTGCA:C	donor_gain	1.0000
3:120641690:CATC:C	acceptor_gain	1.0000
3:120641691:ATCC:A	acceptor_loss	1.0000
3:120641692:TC:T	acceptor_gain	1.0000
3:120641692:TCCT:T	acceptor_loss	1.0000
3:120641693:CC:C	acceptor_gain	1.0000
3:120641694:C:A	acceptor_loss	1.0000
3:120641694:C:CC	acceptor_gain	1.0000
3:120641695:T:G	acceptor_loss	1.0000
3:120644313:CTTTA:C	donor_loss	1.0000
3:120644314:TTTA:T	donor_loss	1.0000
3:120644315:TTAC:T	donor_loss	1.0000
3:120644316:TAC:T	donor_loss	1.0000
3:120644317:ACC:A	donor_loss	1.0000
3:120646969:CAAC:C	donor_loss	1.0000
3:120646972:CC:C	donor_loss	1.0000
3:120647051:AA:A	acceptor_gain	1.0000
3:120647053:C:CC	acceptor_gain	1.0000
3:120650769:CTTA:C	donor_loss	1.0000
3:120650770:TTACC:T	donor_loss	1.0000
3:120650771:TA:T	donor_loss	1.0000

AlphaMissense

2958 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:120674930:G:C	F49L	0.999
3:120674930:G:T	F49L	0.999
3:120674932:A:G	F49L	0.999
3:120638458:G:C	H335D	0.998
3:120641666:A:G	W268R	0.998
3:120641666:A:T	W268R	0.998
3:120652645:A:G	W97R	0.998
3:120652645:A:T	W97R	0.998
3:120670532:G:C	S59R	0.998
3:120670532:G:T	S59R	0.998
3:120674902:T:G	S59R	0.998
3:120633313:T:A	E341V	0.997
3:120633324:G:C	N337K	0.997
3:120633324:G:T	N337K	0.997
3:120641659:C:A	G270V	0.997
3:120641659:C:T	G270E	0.997
3:120641660:C:A	G270W	0.997
3:120644428:G:T	A222D	0.997
3:120674931:A:C	F49C	0.997
3:120633312:C:A	E341D	0.996
3:120633312:C:G	E341D	0.996
3:120638507:G:C	F318L	0.996
3:120638507:G:T	F318L	0.996
3:120638509:A:G	F318L	0.996
3:120638523:G:T	A313D	0.996
3:120638559:A:G	L301S	0.996
3:120641669:C:G	A267P	0.996
3:120644413:A:G	F227S	0.996
3:120646267:C:A	G217W	0.996
3:120647013:C:A	G170V	0.996

dbSNP variants (sampled 300 via entrez): RS1000021448 (3:120647307 G>T), RS1000027419 (3:120630737 A>G), RS1000179213 (3:120683108 G>C), RS1000186434 (3:120682822 A>G,T), RS1000227111 (3:120667210 C>A,T), RS1000253059 (3:120667677 C>T), RS1000264914 (3:120653468 G>A), RS1000278961 (3:120633519 C>CAGCTCT), RS1000346435 (3:120655580 T>G), RS1000422980 (3:120631668 G>A,C), RS1000424398 (3:120673363 T>A), RS1000454081 (3:120649133 C>T), RS1000459618 (3:120663382 T>A), RS1000485579 (3:120637841 C>T), RS1000533660 (3:120679111 T>C)

Disease associations

OMIM: gene MIM:607474 | disease phenotypes: MIM:203500

GenCC curated gene-disease

Disease	Classification	Inheritance
alkaptonuria	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
alkaptonuria	Definitive	AR

Mondo (1): alkaptonuria (MONDO:0008753)

Orphanet (1): Alkaptonuria (Orphanet:56)

HPO phenotypes

65 total (30 of 65 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000024	Prostatitis
HP:0000364	Hearing abnormality
HP:0000366	Abnormality of the nose
HP:0000501	Glaucoma
HP:0000504	Abnormality of vision
HP:0000787	Nephrolithiasis
HP:0000821	Hypothyroidism
HP:0000822	Hypertension
HP:0001000	Abnormality of skin pigmentation
HP:0001369	Arthritis
HP:0001373	Joint dislocation
HP:0001386	Joint swelling
HP:0001387	Joint stiffness
HP:0001507	Growth abnormality
HP:0001597	Abnormal nail morphology
HP:0001650	Aortic valve stenosis
HP:0001653	Mitral regurgitation
HP:0001654	Abnormal heart valve morphology
HP:0001658	Myocardial infarction
HP:0001717	Coronary artery calcification
HP:0001718	Mitral stenosis
HP:0001878	Hemolytic anemia
HP:0002621	Atherosclerosis
HP:0002650	Scoliosis
HP:0002659	Increased susceptibility to fractures
HP:0002758	Osteoarthritis
HP:0002808	Kyphosis
HP:0002829	Arthralgia
HP:0002948	Vertebral fusion

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D000474	Alkaptonuria	C16.320.565.100.187; C18.452.648.100.187

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

38 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases methylation	3
Cyclosporine	decreases expression	3
Progesterone	affects cotreatment, increases expression, decreases expression	2
Aflatoxin B1	affects expression, decreases methylation	2
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
belinostat	decreases expression	1
2-amino-14,16-dimethyloctadecan-3-ol	decreases expression	1
ormosil	affects binding, decreases expression	1
(+)-JQ1 compound	decreases expression	1
theaflavin-3,3’-digallate	affects expression	1
Zoledronic Acid	decreases expression	1
Vorinostat	decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression	1
Arsenic	affects methylation	1
Atrazine	increases expression	1
Azacitidine	increases expression	1
Benzene	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Lipopolysaccharides	affects cotreatment, increases expression	1
Nickel	decreases expression	1
Polyethylene Glycols	affects binding, decreases expression	1
Silicon Dioxide	decreases expression	1

Clinical trials (associated diseases)

10 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01916382	PHASE3	UNKNOWN	Suitability of Nitisinone in Alkaptonuria 2
NCT00107783	PHASE2	COMPLETED	Long-Term Study of Nitisinone to Treat Alkaptonuria
NCT01828463	PHASE2	COMPLETED	Dose Response Study of Nitisinone in Alkaptonuria
NCT01390077	PHASE2/PHASE3	COMPLETED	Nitisinone (NTBC) In Different Age Groups Of Patients With Alkaptonuria
NCT00005909	Not specified	RECRUITING	Study of Alkaptonuria
NCT04142671	Not specified	UNKNOWN	Individualised Gait Modification Strategies in Alkaptonuria Patients
NCT04196959	Not specified	COMPLETED	Evaluation of TYR Sphere
NCT04510142	Not specified	COMPLETED	Questionnaire Follow=up Study Sonia 2
NCT04761588	Not specified	COMPLETED	Evaluation of TYR Sphere in France
NCT06298292	Not specified	NOT_YET_RECRUITING	Acceptability/Tolerance of Protein Substitutes in Tablet Form for the Dietary Management of Rare Aminoacidopathies