VARS1

Chr 6AR

valyl-tRNA synthetase 1

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

Catalyzes the attachment of valine to tRNA(Val)

OMIM ResearchGenerating clinical summary…

GOFmechanismARLOEUF 0.511 OMIM phenotype

Clinical Summary— VARS1

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Gene-Disease Validity (ClinGen)

neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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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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

This gene — mechanism propensity

0.5966th %ile

GOF

0.6638th %ile

LOF

0.3452th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.