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…

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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ClinVar Variants

36 unique Pathogenic / Likely Pathogenic· 239 VUS of 365 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?

0.51LOEUF

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.

ClinVar Variant Classifications

365 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic14

Likely Pathogenic22

VUS239

Likely Benign45

Benign13

Conflicting7

Pathogenic

Likely Pathogenic

239

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	10	4	0	0	14
Likely Pathogenic	11	10	1	0	22
VUS	2	228	6	3	239
Likely Benign	0	14	4	27	45
Benign	0	6	1	6	13
Conflicting	—				7
Total	23	262	12	36	340

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

View in ClinVar →

7 pathogenic / likely-pathogenic (of 11) ClinVar copy-number / structural variants overlap VARS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →