EARS2

Chr 16AR

glutamyl-tRNA synthetase 2, mitochondrial

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

NCBI Gene: 124454ENSG00000103356UniProt: Q5JPH6

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]

Primary Disease Associations & Inheritance

Combined oxidative phosphorylation deficiency 12MIM #614924
AR
430
ClinVar variants
55
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— EARS2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
55 Pathogenic / Likely Pathogenic· 187 VUS of 430 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.11Z-score
OE missense 0.98 (0.89–1.08)
303 obs / 308.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.67 (0.45–1.02)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.98 (0.89–1.08)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.05
0≤1.21.6
LoF obs/exp: 16 / 23.8Missense obs/exp: 303 / 308.3Syn Z: -0.45

ClinVar Variant Classifications

430 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic36
Likely Pathogenic19
VUS187
Likely Benign95
Benign26
Conflicting27
36
Pathogenic
19
Likely Pathogenic
187
VUS
95
Likely Benign
26
Benign
27
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
4
1
31
0
36
Likely Pathogenic
5
9
5
0
19
VUS
3
148
32
4
187
Likely Benign
0
2
36
57
95
Benign
0
2
22
2
26
Conflicting
—27
Total1216212663390

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.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Combined oxidative phosphorylation deficiency 12

MIM #614924

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre.
Pronicka E et al.·J Transl Med
2016
Phenotyping mitochondrial glutamyl-tRNA synthetase deficiency (EARS2): A case series and systematic literature review.
Pelayo G et al.·Neurobiol Dis
2024Case report
Metabolic impact of pathogenic variants in the mitochondrial glutamyl-tRNA synthetase EARS2.
Ni M et al.·J Inherit Metab Dis
2021
Identification of a Novel Variant in EARS2 Associated with a Severe Clinical Phenotype Expands the Clinical Spectrum of LTBL.
Barbosa-Gouveia S et al.·Genes (Basel)
2020
Leukoencephalopathy with thalamus and brainstem involvement and high lactate 'LTBL' caused by EARS2 mutations.
Steenweg ME et al.·Brain
2012
Mitochondrial aminoacyl-tRNA synthetase disorders: an emerging group of developmental disorders of myelination.
Fine AS et al.·J Neurodev Disord
2019Review
Identification of Potential Causal Genes for Neurodegenerative Diseases by Mitochondria-Related Genome-Wide Mendelian Randomization.
Yin KF et al.·Mol Neurobiol
2025
Proteomic-based stratification of intermediate-risk prostate cancer patients.
Zhong Q et al.·Life Sci Alliance
2023Cohort
Mitochondrial aminoacyl-tRNA synthetases trigger unique compensatory mechanisms in neurons.
Podmanicky O et al.·Hum Mol Genet
2024Functional
Neuropathological hallmarks of antenatal mitochondrial diseases with a corpus callosum defect.
Boutaud L et al.·Brain
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools