VARS1

Chr 6AR

valyl-tRNA synthetase 1

Also known as: G7A, NDMSCA, VARS, VARS2

NCBI Gene: 7407 ENSG00000204394 UniProt: P26640 OMIM: 192150

The protein catalyzes the attachment of valine to tRNA(Val), an essential step in protein synthesis. Mutations cause autosomal recessive neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy. The gene is highly constrained against loss-of-function variants (LOEUF 0.511), reflecting its critical role in cellular protein synthesis.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. The protein encoded by this gene belongs to class-I aminoacyl-tRNA synthetase family and is located in the class III region of the major histocompatibility complex. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophyMIM #617802

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy · AR · ClinGen 2023

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.51

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.51LOEUF

pLI 0.000

Z-score 4.98

OE 0.37 (0.27–0.51)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.68Z-score

OE missense 0.73 (0.68–0.78)

577 obs / 789.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.37 (0.27–0.51)

0≤0.351.4

Missense OE?0.73 (0.68–0.78)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 27 / 72.9Missense obs/exp: 577 / 789.3Syn Z: 1.99

Background carrier burden — how many people carry a rare variant somewhere in VARS1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 40

1,430 rare PASS variants

Rare truncating (LoF)

1 in 1,000

194 rare PASS variants

Rare synonymous (reference)

1 in 55

645 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for VARS1. 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 44	1 in 1,100
South Asian	~43k	1 in 43	1 in 2,500
Remaining (unassigned)	~30k	1 in 36	1 in 880
European (Finnish)	~27k	1 in 100	1 in 1,100
Admixed American	~22k	1 in 44	1 in 1,300
African / African American	~21k	1 in 49	1 in 1,200
East Asian	~20k	1 in 44	1 in 960
Ashkenazi Jewish	~13k	1 in 150	≈ 1 in 4,400
Middle Eastern	~2,884	1 in 40	≈ 1 in 2,900

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): All 29 coding exons well covered in gnomAD exomes and genomes.? see exons ↓