CARS2

Chr 13AR

cysteinyl-tRNA synthetase 2, mitochondrial

Also known as: COXPD27, cysRS

NCBI Gene: 79587ENSG00000134905UniProt: Q9HA77OMIM: 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.

OMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
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
21 unique Pathogenic / Likely Pathogenic· 114 VUS of 300 total submissions
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Clinical Trials
2 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 OE0.55 (0.37–0.84)
0≤0.351.4
Missense OE0.96 (0.88–1.05)
0≤0.61.4
Synonymous OE1.08
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

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

DN
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

300 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19
Likely Pathogenic2
VUS114
Likely Benign142
Benign3
Conflicting1
19
Pathogenic
2
Likely Pathogenic
114
VUS
142
Likely Benign
3
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
19
0
19
Likely Pathogenic
2
0
0
0
2
VUS
10
90
13
1
114
Likely Benign
0
0
71
71
142
Benign
0
0
3
0
3
Conflicting
—1
Total129010672281

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

View in ClinVar →

Protein Context — Lollipop Plot

CARS2 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Cars2-Mediated Cysteine Catabolism Drives Brown Fat Development and Thermogenesis Through Persulfidating EBF2.
Peng X et al.·Adv Sci (Weinh)
2026
The Childhood Autism Rating Scale Second Edition (CARS2) and Its Applicability in an Iranian Sample.
Samadi SA et al.·Autism Res
2025Open Access
Whole exome sequencing identified five novel variants in CNTN2, CARS2, ARSA, and CLCN4 leading to epilepsy in consanguineous families.
Abdulkareem AA et al.·Front Genet
2023Open Access
Severe neonatal onset neuroregression with paroxysmal dystonia and apnoea: Expanding the phenotypic and genotypic spectrum of CARS2-related mitochondrial disease.
Poquérusse J et al.·JIMD Rep
2023Open Access
Comparing the Indian Autism Screening Questionnaire (IASQ) and the Indian Scale for Assessment of Autism (ISAA) with the Childhood Autism Rating Scale-Second Edition (CARS2) in Indian settings.
Chakraborty S et al.·PLoS One
2022Open Access
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients