UROS

Chr 10AR

uroporphyrinogen III synthase

Also known as: Mgu, UROIIIS

NCBI Gene: 7390 ENSG00000188690 UniProt: P10746 OMIM: 606938

The encoded protein catalyzes the cyclization of hydroxymethylbilane to uroporphyrinogen III, a critical step in heme biosynthesis that serves as the branch point for porphyrin synthesis pathways. Mutations cause congenital erythropoietic porphyria (Gunther's disease), which follows autosomal recessive inheritance and typically presents in early infancy with severe photosensitivity, hemolytic anemia, and cutaneous manifestations. The gene shows relatively low constraint to loss-of-function variation (pLI = 0.03, LOEUF = 0.73), consistent with the recessive inheritance pattern.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene catalyzes the fourth step of porphyrin biosynthesis in the heme biosynthetic pathway. Defects in this gene cause congenital erythropoietic porphyria (Gunther's disease). [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.731 OMIM phenotype

Clinical Summary— UROS

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Gene-Disease Validity (ClinGen)

cutaneous porphyria · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.35) despite low pLI — interpret in context.

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ClinVar Variants

33 unique Pathogenic / Likely Pathogenic· 52 VUS of 166 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — UROS

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?

0.73LOEUF

pLI 0.032

Z-score 2.31

OE 0.35 (0.18–0.73)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.08Z-score

OE missense 1.02 (0.89–1.17)

142 obs / 139.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.35 (0.18–0.73)

0≤0.351.4

Missense OE?1.02 (0.89–1.17)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 5 / 14.5Missense obs/exp: 142 / 139.3Syn Z: 0.32

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveUROS-related congenital erythropoietic porphyriaLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.73top 25%

GOF

0.4678th %ile

LOF

0.2289th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

166 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27

Likely Pathogenic6

VUS52

Likely Benign42

Benign26

Conflicting5

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	5	15	7	0	27
Likely Pathogenic	3	2	1	0	6
VUS	0	42	10	0	52
Likely Benign	0	6	18	18	42
Benign	0	1	22	3	26
Conflicting	—				5
Total	8	66	58	21	158

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

View in ClinVar →

66 pathogenic / likely-pathogenic (of 74) ClinVar copy-number / structural variants overlap UROS — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →