MARS2

Chr 2AR

methionyl-tRNA synthetase 2, mitochondrial

Also known as: COXPD25, MetRS, mtMetRS

NCBI Gene: 92935ENSG00000247626UniProt: Q96GW9

This gene produces a mitochondrial methionyl-tRNA synthetase protein that is encoded by the nuclear genome and imported to the mitochondrion. This protein likely functions as a monomer and is predicted to localize to the mitochondrial matrix. Mutations in this gene are associated with the autosomal recessive neurodegenerative disease spastic ataxia-3 (SPAX3). [provided by RefSeq, Apr 2014]

Primary Disease Associations & Inheritance

?Combined oxidative phosphorylation deficiency 25MIM #616430
AR
Spastic ataxia 3, autosomal recessiveMIM #611390
AR
350
ClinVar variants
43
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— MARS2
🧬
Gene-Disease Validity (ClinGen)
mitochondrial disease · 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
43 Pathogenic / Likely Pathogenic· 221 VUS of 350 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.
0.87LOEUF
pLI 0.000
Z-score 1.99
OE 0.51 (0.32–0.87)
Tolerant

Typical tolerance to LoF variation

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.
0.30Z-score
OE missense 0.95 (0.87–1.05)
316 obs / 331.3 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.0.51 (0.32–0.87)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.95 (0.87–1.05)
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.1.11
0≤1.21.6
LoF obs/exp: 10 / 19.5Missense obs/exp: 316 / 331.3Syn Z: -1.02

ClinVar Variant Classifications

350 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic40
Likely Pathogenic3
VUS221
Likely Benign70
Benign8
Conflicting8
40
Pathogenic
3
Likely Pathogenic
221
VUS
70
Likely Benign
8
Benign
8
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
0
38
0
40
Likely Pathogenic
0
1
2
0
3
VUS
4
189
14
14
221
Likely Benign
0
6
4
60
70
Benign
0
1
2
5
8
Conflicting
—8
Total61976079350

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

View in ClinVar →

Protein Context — Lollipop Plot

MARS2 · 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 25

MIM #616430

Molecular basis of disorder known

Autosomal recessive

Spastic ataxia 3, autosomal recessive

MIM #611390

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Uncovering heterogeneity in sepsis: a comparative analysis of subphenotypes.
van Amstel RBE et al.·Intensive Care Med
2023
Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study.
Scicluna BP et al.·Lancet Respir Med
2017Cohort
Clinical subtypes in critically ill patients with sepsis: validation and parsimonious classifier model development.
van Amstel RBE et al.·Crit Care
2025Cohort
Mitochondrial-related genes as prognostic and metastatic markers in breast cancer: insights from comprehensive analysis and clinical models.
Fang Y et al.·Front Immunol
2024Functional
Novel, compound heterozygous, single-nucleotide variants in MARS2 associated with developmental delay, poor growth, and sensorineural hearing loss.
Webb BD et al.·Hum Mutat
2015
Management of Advanced Pleural Mesothelioma-At the Crossroads.
Nowak AK et al.·JCO Oncol Pract
2022Review
Generation of induced pluripotent stem cell line ISMMSi060-A from a patient with combined oxidative phosphorylation deficiency 25.
Salemi SE et al.·Stem Cell Res
2025
Mutations in the mitochondrial methionyl-tRNA synthetase cause a neurodegenerative phenotype in flies and a recessive ataxia (ARSAL) in humans.
Bayat V et al.·PLoS Biol
2012
Exome Sequencing of a Type 1 Diabetes Mellitus Family Exposes Both Common and Individualized Rare Variants Contributing to Pathogenesis.
Ibrahim TAM et al.·J Diabetes Res
2025
Construction and validation of a robust prognostic model based on immune features in sepsis.
Zheng Y et al.·Front Immunol
2022Functional
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