MARS2

Chr 2AR

methionyl-tRNA synthetase 2, mitochondrial

Also known as: COXPD25, MetRS, mtMetRS

NCBI Gene: 92935 ENSG00000247626 UniProt: Q96GW9 OMIM: 609728

The MARS2 protein is a mitochondrial methionyl-tRNA synthetase that charges tRNA with methionine for mitochondrial protein synthesis. Mutations cause autosomal recessive spastic ataxia-3 (SPAX3), a neurodegenerative disorder, and combined oxidative phosphorylation deficiency 25. The gene shows low constraint against loss-of-function variants (pLI ~0), making homozygous or compound heterozygous mutations the likely disease mechanism in this autosomal recessive condition.

OMIM ResearchSummary from RefSeq, OMIM

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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.872 OMIM phenotypes

Clinical Summary— MARS2

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

8 unique Pathogenic / Likely Pathogenic· 219 VUS of 313 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.87LOEUF

pLI 0.000

Z-score 1.99

OE 0.51 (0.32–0.87)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.30Z-score

OE missense 0.95 (0.87–1.05)

316 obs / 331.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.51 (0.32–0.87)

0≤0.351.4

Missense OE?0.95 (0.87–1.05)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 10 / 19.5Missense obs/exp: 316 / 331.3Syn Z: -1.02

This gene — mechanism propensity

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

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic3

VUS219

Likely Benign70

Benign8

Conflicting8

Pathogenic

Likely Pathogenic

219

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
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
Total	16	200	10	79	313

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 →