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…

Primary Disease Associations & Inheritance

AlkaptonuriaMIM #203500

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · alkaptonuria · AR · ClinGen 2020

Active trials

226

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.94

LOEUF

Mechanism· predicted

📖

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

Background carrier burden — how many people carry a rare variant somewhere in HGD?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 80

615 rare PASS variants

Rare truncating (LoF)

1 in 1,100

125 rare PASS variants

Rare synonymous (reference)

1 in 220

207 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for HGD. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 120	1 in 1,100
South Asian	~43k	1 in 98	1 in 530
Remaining (unassigned)	~30k	1 in 75	1 in 330
European (Finnish)	~27k	1 in 510	1 in 1,700
Admixed American	~22k	1 in 90	1 in 1,600
African / African American	~21k	1 in 130	1 in 1,900
East Asian	~20k	1 in 130	1 in 2,800
Ashkenazi Jewish	~13k	1 in 500	none seen
Middle Eastern	~2,884	1 in 140	≈ 1 in 2,800

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 13 of 14 coding exons well covered in gnomAD exomes; exon 4 marginal. Genomes: all 14.? see exons ↓