MARS2

Chr 2AR

methionyl-tRNA synthetase 2, mitochondrial

Also known as: COXPD25, MetRS, mtMetRS

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]

OMIMResearchGenerating clinical summary…
MultiplemechanismARLOEUF 0.872 OMIM phenotypes
Clinical SummaryMARS2
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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.
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ClinVar Variants
8 unique Pathogenic / Likely Pathogenic· 219 VUS of 313 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint?
0.87LOEUF
pLI 0.000
Z-score 1.99
OE 0.51 (0.320.87)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?
0.30Z-score
OE missense 0.95 (0.871.05)
316 obs / 331.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?
LoF OE?0.51 (0.320.87)
00.351.4
Missense OE?0.95 (0.871.05)
00.61.4
Synonymous OE?1.11
01.21.6
LoF obs/exp: 10 / 19.5Missense obs/exp: 316 / 331.3Syn Z: -1.02

This gene — mechanism propensity

DN
0.6454th %ile
GOF
0.6541th %ile
LOF
0.3357th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median
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

313 submitted variants in ClinVar

Classification Summary

Pathogenic5
Likely Pathogenic3
VUS219
Likely Benign70
Benign8
Conflicting8
5
Pathogenic
3
Likely Pathogenic
219
VUS
70
Likely Benign
8
Benign
8
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
0
2
0
5
Likely Pathogenic
1
2
0
0
3
VUS
12
191
2
14
219
Likely Benign
0
6
4
60
70
Benign
0
1
2
5
8
Conflicting
8
Total162001079313

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

View in ClinVar →

36 pathogenic / likely-pathogenic (of 39) ClinVar copy-number / structural variants overlap MARS2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

MARS2 · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →