CARS2

Chr 13AR

cysteinyl-tRNA synthetase 2, mitochondrial

Also known as: COXPD27, cysRS

NCBI Gene: 79587ENSG00000134905UniProt: Q9HA77

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]

Primary Disease Associations & Inheritance

Combined oxidative phosphorylation deficiency 27MIM #616672
AR
986
ClinVar variants
20
Pathogenic / LP
0.00
pLI score
2
Active trials
Clinical Summary— CARS2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
20 Pathogenic / Likely Pathogenic· 114 VUS of 986 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

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.
0.84LOEUF
pLI 0.000
Z-score 2.23
OE 0.55 (0.37–0.84)
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.
0.25Z-score
OE missense 0.96 (0.88–1.05)
318 obs / 330.8 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.0.55 (0.37–0.84)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.96 (0.88–1.05)
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.1.08
0≤1.21.6
LoF obs/exp: 16 / 28.9Missense obs/exp: 318 / 330.8Syn Z: -0.73

ClinVar Variant Classifications

986 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19
Likely Pathogenic1
VUS114
Likely Benign143
Benign3
Conflicting1
19
Pathogenic
1
Likely Pathogenic
114
VUS
143
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
1
0
0
0
1
VUS
7
89
17
1
114
Likely Benign
0
0
72
71
143
Benign
0
0
3
0
3
Conflicting
—1
Total88911172281

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.

Gene2Phenotype Curations

CARS2-related epileptic encephalopathy with complex movement disorder and regression

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Combined oxidative phosphorylation deficiency 27

MIM #616672

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Emerging roles of hydrogen sulfide-metabolizing enzymes in cancer.
Dawoud A et al.·Redox Rep
2024Review
Folate receptor alpha autoantibodies in children with autism spectrum disorder.
Phunsawat P et al.·Biomarkers
2022
Bumetanide oral solution for the treatment of children and adolescents with autism spectrum disorder: Results from two randomized phase III studies.
Fuentes J et al.·Autism Res
2023Clinical trial
Sex/Gender Differences in CARS2 and GARS-3 Item Scores: Evidence of Phenotypic Differences Between Males and Females with ASD.
Tsirgiotis JM et al.·J Autism Dev Disord
2022
A novel anti-inflammatory role links the CARS2 locus to protection from coronary artery disease.
Dang AT et al.·Atherosclerosis
2022
Clinicopathologic Findings of CARS2 Mutation.
Samanta D et al.·Pediatr Neurol
2018Case report
Feasibility and acceptability of the Indian Autism Screening Questionnaire in clinical and community settings.
Antony N et al.·PLoS One
2023
Routine Diagnostics Confirm Novel Neurodevelopmental Disorders.
Jauss RT et al.·Genes (Basel)
2022
A homozygous splice-site mutation in CARS2 is associated with progressive myoclonic epilepsy.
Hallmann K et al.·Neurology
2014Case report
The Relationship Between the Childhood Autism Rating Scale: Second Edition and Clinical Diagnosis Utilizing the DSM-IV-TR and the DSM-5.
Dawkins T et al.·J Autism Dev Disord
2016
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
Phelan-McDermid SyndromeSHANK3 Haploinsufficiency

RB001 Gene Therapy Study in Children With SHANK3-related Phelan McDermid Syndrome (PMS)

RECRUITING
NCT07014020Phase NAPeking University First HospitalStarted 2025-06-16
RB001
Autism Spectrum DisorderEosinophilic Gastrointestinal Disorders

Umbilical Cord Blood Therapy in a Child With Eosinophilic Duodenitis and Autism Spectrum Disorder: a Case Study

NOT YET RECRUITING
NCT06995274Phase NABundang CHA HospitalStarted 2025-06-01
Umbilical Cord Blood Infusion (Autologous and Allogeneic)

External Resources

Links to major genomics databases and tools