EARS2

Chr 16AR

glutamyl-tRNA synthetase 2, mitochondrial

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

NCBI Gene: 124454 ENSG00000103356 UniProt: Q5JPH6 OMIM: 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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the class I family of aminoacyl-tRNA synthetases. These enzymes play a critical role in protein biosynthesis by charging tRNAs with their cognate amino acids. This protein is encoded by the nuclear genome but is likely to be imported to the mitochondrion where it is thought to catalyze the ligation of glutamate to tRNA molecules. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency 12 (COXPD12). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

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

41 unique Pathogenic / Likely Pathogenic· 189 VUS of 394 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 OE?0.67 (0.45–1.02)

0≤0.351.4

Missense OE?0.98 (0.89–1.08)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 16 / 23.8Missense obs/exp: 303 / 308.3Syn Z: -0.45

This gene — mechanism propensity

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

394 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19

Likely Pathogenic22

VUS189

Likely Benign97

Benign33

Conflicting27

Pathogenic

Likely Pathogenic

189

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	11	4	4	0	19
Likely Pathogenic	10	12	0	0	22
VUS	4	153	28	4	189
Likely Benign	0	4	36	57	97
Benign	0	3	24	6	33
Conflicting	—				27
Total	25	176	92	67	387

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

View in ClinVar →

30 pathogenic / likely-pathogenic (of 38) ClinVar copy-number / structural variants overlap EARS2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →