ETHE1

Chr 19AR

ETHE1 persulfide dioxygenase

Also known as: HSCO, YF13H12

NCBI Gene: 23474ENSG00000105755UniProt: O95571OMIM: 608451

The ETHE1 protein is a sulfur dioxygenase that catalyzes the oxidation of persulfide substrates in the mitochondrial sulfide oxidation pathway, preventing toxic accumulation of hydrogen sulfide that can inhibit cytochrome c oxidase. Mutations cause ethylmalonic encephalopathy, an infantile-onset metabolic disorder affecting the brain, gastrointestinal tract, and peripheral vessels with autosomal recessive inheritance. This gene shows relatively low constraint against loss-of-function variants (pLI near zero, LOEUF 1.46).

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismARLOEUF 1.461 OMIM phenotype
VCEP Guidelines: Mitochondrial DiseaseReleased
View SpecificationsClinGen Panel
Clinical Summary— ETHE1
🧬
Gene-Disease Validity (ClinGen)
Leigh syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
82 unique Pathogenic / Likely Pathogenic· 86 VUS of 404 total submissions
Explore recent and relevant literature in Research Assistant →
📖
GeneReview available — ETHE1
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
1.46LOEUF
pLI 0.000
Z-score 0.49
OE 0.84 (0.50–1.46)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
0.96Z-score
OE missense 0.77 (0.66–0.91)
110 obs / 142.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.84 (0.50–1.46)
0≤0.351.4
Missense OE0.77 (0.66–0.91)
0≤0.61.4
Synonymous OE0.93
0≤1.21.6
LoF obs/exp: 9 / 10.7Missense obs/exp: 110 / 142.1Syn Z: 0.45
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveETHE1-related ethylmalonic encephalopathyLOFAR

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

DN
0.6744th %ile
GOF
0.5857th %ile
LOF
0.4331th %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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

404 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic30
Likely Pathogenic52
VUS86
Likely Benign210
Benign12
Conflicting5
30
Pathogenic
52
Likely Pathogenic
86
VUS
210
Likely Benign
12
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
19
5
6
0
30
Likely Pathogenic
42
7
3
0
52
VUS
1
65
15
5
86
Likely Benign
1
1
88
120
210
Benign
0
0
12
0
12
Conflicting
—5
Total6378124125395

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

View in ClinVar →

Protein Context — Lollipop Plot

ETHE1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
An atypically mild case of ethylmalonic encephalopathy with pathogenic ETHE1 variant.
Kashima DT et al.·Am J Med Genet A
2023Case report
Hydrogen sulfide as an anti-calcification stratagem in human aortic valve: Altered biogenesis and mitochondrial metabolism of H(2)S lead to H(2)S deficiency in calcific aortic valve disease.
Combi Z et al.·Redox Biol
2023
ETHE1 dampens colorectal cancer angiogenesis by promoting TC45 Dephosphorylation of STAT3 to inhibit VEGF-A expression.
She X et al.·Cell Death Dis
2024
Deficiency of the mitochondrial sulfide regulator ETHE1 disturbs cell growth, glutathione level and causes proteome alterations outside mitochondria.
Sahebekhtiari N et al.·Biochim Biophys Acta Mol Basis Dis
2019
Ethylmalonic Encephalopathy: a literature review and two new cases of mild phenotype.
Platt I et al.·Neurol Sci
2023Review
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients