WARS1
Chr 14ARADtryptophanyl-tRNA synthetase 1
Also known as: GAMMA-2, HMN9, HMND9, IFI53, IFP53, NEDMSBA, WARS
The protein catalyzes the aminoacylation of tRNA with tryptophan in the cytoplasm, a critical step in protein synthesis. Mutations cause neurodevelopmental disorder with microcephaly and speech delay with or without brain abnormalities (autosomal recessive) and distal hereditary motor neuronopathy type 9 (autosomal dominant). The pathogenic mechanism involves disruption of cytoplasmic protein synthesis due to impaired tryptophan incorporation into nascent proteins.
Limited evidence — not for standalone diagnostic reporting
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
More LoF-intolerant than ~75% of genes
Mild missense constraint
The highest-scoring mechanism for this gene is dominant-negative.
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.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
186 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 1 | 35 | 0 | 36 |
Likely Pathogenic | 1 | 2 | 1 | 0 | 4 |
VUS | 3 | 74 | 7 | 0 | 84 |
Likely Benign | 0 | 7 | 5 | 12 | 24 |
Benign | 0 | 1 | 13 | 1 | 15 |
Conflicting | — | 5 | |||
| Total | 4 | 85 | 61 | 13 | 168 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
WARS1 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Host Response to Infection by Direct Analysis of Leukocyte Single Cell-type Gene Expression/transcript Abundance, Direct LS-TA
ACTIVE NOT RECRUITINGHost Response to Infection by Direct Analysis of Leukocyte Single Cell-type Gene Expression/transcript Abundance, Direct LS-TA. a Prospective Study Will Evaluate the Performance of Direct LS-TA in Triage Febrile Patients Into Major Categories of Infections: Viral, Bacterial or Active Tuberculosis.
NOT YET RECRUITINGExternal Resources
Links to major genomics databases and tools