EARS2

Chr 16AR

glutamyl-tRNA synthetase 2, mitochondrial

Also known as: COXPD12, MSE1, gluRS, mtGlnRS, mtGluRS

NCBI Gene: 124454ENSG00000103356UniProt: Q5JPH6OMIM: 612799

The protein catalyzes the ligation of glutamate to tRNA molecules in the mitochondrial matrix, playing a critical role in mitochondrial protein biosynthesis. Mutations cause combined oxidative phosphorylation deficiency 12 (COXPD12) through autosomal recessive inheritance. The pathogenic mechanism involves dominant-negative effects that disrupt mitochondrial protein synthesis and subsequent oxidative phosphorylation.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
DNmechanismARLOEUF 1.021 OMIM phenotype
Clinical Summary— EARS2
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Gene-Disease Validity (ClinGen)
Leigh syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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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
60 unique Pathogenic / Likely Pathogenic· 144 VUS of 329 total submissions
Explore recent and relevant literature in Research Assistant →
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GeneReview available — EARS2
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
1.02LOEUF
pLI 0.000
Z-score 1.48
OE 0.67 (0.45–1.02)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
0.11Z-score
OE missense 0.98 (0.89–1.08)
303 obs / 308.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.67 (0.45–1.02)
0≤0.351.4
Missense OE0.98 (0.89–1.08)
0≤0.61.4
Synonymous OE1.05
0≤1.21.6
LoF obs/exp: 16 / 23.8Missense obs/exp: 303 / 308.3Syn Z: -0.45
DN
0.6841th %ile
GOF
0.5760th %ile
LOF
0.2969th %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

329 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic37
Likely Pathogenic23
VUS144
Likely Benign72
Benign26
Conflicting20
37
Pathogenic
23
Likely Pathogenic
144
VUS
72
Likely Benign
26
Benign
20
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
8
4
25
0
37
Likely Pathogenic
9
11
3
0
23
VUS
4
114
24
2
144
Likely Benign
0
4
18
50
72
Benign
0
3
17
6
26
Conflicting
—20
Total211368758322

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

View in ClinVar →

Protein Context — Lollipop Plot

EARS2 · 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 4 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
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