HGD

Chr 3AR

homogentisate 1,2-dioxygenase

Also known as: AKU, HGO

NCBI Gene: 3081 ENSG00000113924 UniProt: Q93099 OMIM: 607474

This gene encodes homogentisate 1,2-dioxygenase, which catalyzes the conversion of homogentisate to maleylacetoacetate in the tyrosine and phenylalanine catabolic pathway. Mutations cause alkaptonuria, an autosomal recessive metabolic disorder. The gene is highly constrained against loss-of-function variants (LOEUF 0.936), indicating evolutionary intolerance to functional disruption.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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.[provided by RefSeq, May 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.941 OMIM phenotype

Clinical Summary— HGD

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Gene-Disease Validity (ClinGen)

alkaptonuria · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

278 unique Pathogenic / Likely Pathogenic· 135 VUS of 640 total submissions

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — HGD

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.94LOEUF

pLI 0.000

Z-score 1.81

OE 0.62 (0.42–0.94)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.29Z-score

OE missense 0.95 (0.85–1.06)

223 obs / 235.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.62 (0.42–0.94)

0≤0.351.4

Missense OE?0.95 (0.85–1.06)

0≤0.61.4

Synonymous OE?1.26

0≤1.21.6

LoF obs/exp: 16 / 26.0Missense obs/exp: 223 / 235.5Syn Z: -1.86

This gene — mechanism propensity

0.6357th %ile

GOF

0.4777th %ile

LOF

0.3745th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

640 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic183

Likely Pathogenic95

VUS135

Likely Benign182

Benign13

Conflicting24

183

Pathogenic

Likely Pathogenic

135

VUS

182

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	73	89	18	3	183
Likely Pathogenic	49	41	3	2	95
VUS	2	110	21	2	135
Likely Benign	0	4	76	102	182
Benign	0	2	8	3	13
Conflicting	—				24
Total	124	246	126	112	632

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

17 pathogenic / likely-pathogenic (of 25) ClinVar copy-number / structural variants overlap HGD — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →