VARS1

Chr 6AR

valyl-tRNA synthetase 1

Also known as: G7A, NDMSCA, VARS, VARS2

NCBI Gene: 7407ENSG00000204394UniProt: P26640

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]

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophyMIM #617802
AR
346
ClinVar variants
43
Pathogenic / LP
0.00
pLI score
0
Active trials
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.
📋
ClinVar Variants
43 Pathogenic / Likely Pathogenic· 239 VUS of 346 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.37 (0.27–0.51)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.73 (0.68–0.78)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.86
0≤1.21.6
LoF obs/exp: 27 / 72.9Missense obs/exp: 577 / 789.3Syn Z: 1.99

ClinVar Variant Classifications

346 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20
Likely Pathogenic23
VUS239
Likely Benign44
Benign13
Conflicting7
20
Pathogenic
23
Likely Pathogenic
239
VUS
44
Likely Benign
13
Benign
7
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
4
11
0
20
Likely Pathogenic
5
10
8
0
23
VUS
1
224
11
3
239
Likely Benign
0
14
4
26
44
Benign
0
6
1
6
13
Conflicting
—7
Total112583535346

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

View in 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.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy

MIM #617802

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools