CARS2

Chr 13AR

cysteinyl-tRNA synthetase 2, mitochondrial

Also known as: COXPD27, cysRS

NCBI Gene: 79587 ENSG00000134905 UniProt: Q9HA77 OMIM: 612800

The protein catalyzes the ligation of cysteine to tRNA molecules in mitochondria, playing a critical role in mitochondrial protein biosynthesis. Autosomal recessive mutations cause combined oxidative phosphorylation deficiency 27, which presents as a progressive myoclonic epilepsy with symptoms similar to MERRF syndrome. The pathogenic mechanism involves dominant-negative effects that disrupt mitochondrial translation and oxidative phosphorylation.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a putative 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 cysteine to tRNA molecules. A splice-site mutation in this gene has been associated with a novel progressive myoclonic epilepsy disease with similar symptoms to MERRF syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2017]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.841 OMIM phenotype

Clinical Summary— CARS2

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ARModerate

Moderate evidence — consider for supplementary testing

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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

6 unique Pathogenic / Likely Pathogenic· 386 VUS of 863 total submissions

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

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?

0.84LOEUF

pLI 0.000

Z-score 2.23

OE 0.55 (0.37–0.84)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.25Z-score

OE missense 0.96 (0.88–1.05)

318 obs / 330.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.55 (0.37–0.84)

0≤0.351.4

Missense OE?0.96 (0.88–1.05)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 16 / 28.9Missense obs/exp: 318 / 330.8Syn Z: -0.73

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCARS2-related epileptic encephalopathy with complex movement disorder and regressionLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6646th %ile

GOF

0.6053th %ile

LOF

0.3259th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

863 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic5

VUS386

Likely Benign357

Benign71

Conflicting24

Pathogenic

Likely Pathogenic

386

VUS

357

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	0	0	1
Likely Pathogenic	4	1	0	0	5
VUS	33	313	38	2	386
Likely Benign	0	4	171	182	357
Benign	1	6	60	4	71
Conflicting	—				24
Total	39	324	269	188	844

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

View in ClinVar →

111 pathogenic / likely-pathogenic (of 126) ClinVar copy-number / structural variants overlap CARS2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →