CARS1

Chr 11AR

cysteinyl-tRNA synthetase 1

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

NCBI Gene: 833 ENSG00000110619 UniProt: P49589 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…

Primary Disease Associations & Inheritance

Microcephaly, developmental delay, and brittle hair syndromeMIM #618891

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Microcephaly, developmental delay, and brittle hair syndrome; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.49

LOEUF

LOF

Mechanism· G2P

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

Background carrier burden — how many people carry a rare variant somewhere in CARS1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 53

1,066 rare PASS variants

Rare truncating (LoF)

1 in 1,800

125 rare PASS variants

Rare synonymous (reference)

1 in 74

429 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CARS1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 74	1 in 2,000
South Asian	~43k	1 in 51	1 in 3,800
Remaining (unassigned)	~30k	1 in 47	1 in 2,500
European (Finnish)	~27k	1 in 92	1 in 1,800
Admixed American	~22k	1 in 47	1 in 1,600
African / African American	~21k	1 in 55	1 in 2,000
East Asian	~20k	1 in 57	1 in 700
Ashkenazi Jewish	~13k	1 in 210	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 51	1 in 460

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 21 of 23 coding exons well covered in gnomAD exomes; exons 5, 12 marginal. Genomes: all 23.? see exons ↓