CARS1

Chr 11AR

cysteinyl-tRNA synthetase 1

Also known as: CARS, CYSRS, MCDDBH, MDBH, MGC:11246

NCBI Gene: 833 ENSG00000110619 OMIM: 123859

The protein catalyzes the ATP-dependent ligation of cysteine to tRNA(Cys) as a class 1 aminoacyl-tRNA synthetase essential for protein synthesis. Mutations cause microcephaly, developmental delay, and brittle hair syndrome with autosomal recessive inheritance. The gene is highly constrained against loss-of-function variation (LOEUF 0.494), reflecting its essential cellular role.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a class 1 aminoacyl-tRNA synthetase, cysteinyl-tRNA synthetase. Each of the twenty aminoacyl-tRNA synthetases catalyzes the aminoacylation of a specific tRNA or tRNA isoaccepting family with the cognate amino acid. This gene is one of several located near the imprinted gene domain on chromosome 11p15.5, an important tumor-suppressor gene region. Alterations in this region have been associated with Beckwith-Wiedemann syndrome, Wilms tumor, rhabdomyosarcoma, adrenocortical carcinoma, and lung, ovarian and breast cancers. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Aug 2010]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.491 OMIM phenotype

Clinical Summary— CARS1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.

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ClinVar Variants

7 unique Pathogenic / Likely Pathogenic· 146 VUS of 215 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.49LOEUF

pLI 0.000

Z-score 4.31

OE 0.32 (0.21–0.49)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.20Z-score

OE missense 0.85 (0.78–0.92)

411 obs / 485.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.32 (0.21–0.49)

0≤0.351.4

Missense OE?0.85 (0.78–0.92)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 15 / 46.8Missense obs/exp: 411 / 485.1Syn Z: 0.30

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCARS1-related microcephaly, developmental delay, and brittle hair and nailsLOFAR

This gene — mechanism propensity

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

0.6454th %ile

GOF

0.5661th %ile

LOF

0.3552th %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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

215 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic2

VUS146

Likely Benign32

Benign9

Conflicting2

Pathogenic

Likely Pathogenic

146

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	2	0	0	5
Likely Pathogenic	1	1	0	0	2
VUS	0	146	0	0	146
Likely Benign	0	12	2	18	32
Benign	0	3	2	4	9
Conflicting	—				2
Total	4	164	4	22	196

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

View in ClinVar →

26 pathogenic / likely-pathogenic (of 31) ClinVar copy-number / structural variants overlap CARS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →