VARS1

Chr 6AR

valyl-tRNA synthetase 1

Also known as: G7A, NDMSCA, VARS, VARS2

NCBI Gene: 7407ENSG00000204394UniProt: P26640OMIM: 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.

OMIMResearchSummary from RefSeq, OMIM, UniProt
GOFmechanismARLOEUF 0.511 OMIM phenotype
Clinical Summary— VARS1
🧬
Gene-Disease Validity (ClinGen)
neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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 OE0.37 (0.27–0.51)
0≤0.351.4
Missense OE0.73 (0.68–0.78)
0≤0.61.4
Synonymous OE0.86
0≤1.21.6
LoF obs/exp: 27 / 72.9Missense obs/exp: 577 / 789.3Syn Z: 1.99
DN
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

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

VARS1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Fetal akinesia deformation sequence and massive perivillous fibrin deposition resulting in fetal death in six fetuses from one consanguineous couple, including literature review
Tjon JK et al.·Mol Genet Genomic Med
2021Review
Corrigendum to "Novel VARS1 variants define new clinical and molecular subtypes of a rare neurodevelopmental syndrome" [Biochim. Biophys. Acta Mol. Basis Dis. 1872 (2026)/168184].
Aynekin B et al.·Biochim Biophys Acta Mol Basis Dis
2026
Revisiting Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients with Glioblastoma:Proteomic Alteration and Comparison Analysis with the Standard-of-Care Chemoirradiation
Krauze AV et al.·Biomolecules
2023Cohort
Whole Exome-Wide Association Identifies Rare Variants in GALNT9 Associated with Middle Eastern Papillary Thyroid Carcinoma Risk
Bu R et al.·Cancers (Basel)
2023
Genetic associations in ankylosing spondylitis: circulating proteins as drug targets and biomarkers
Zhang Y et al.·Front Immunol
2024
Top 5 full-text resultsSearch PubTator3 ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients