VARS1 Gene - Valyl-tRNA Synthetase 1
Essential enzyme for protein synthesis and implicated in neurodevelopmental disorders
Gene Information Card
| Symbol | VARS1 |
|---|---|
| Full Name | Valyl-tRNA Synthetase 1 |
| Gene Type | Protein coding |
| Chromosomal Location | 6p21.33 |
| NCBI Gene ID | 7407 ncbi.nlm.nih.gov/gene/7407 |
| Ensembl ID | ENSG00000112210 |
| UniProt ID | P26640 |
| OMIM ID | 192150 |
| HGNC ID | 12651 |
| Aliases | VARS, G7A, VARS2 |
Description
VARS1 encodes the cytoplasmic valyl-tRNA synthetase, a class I aminoacyl-tRNA synthetase that catalyzes the attachment of valine to its cognate tRNA. This enzyme is essential for accurate protein translation. Mutations in VARS1 are associated with autosomal recessive neurodevelopmental disorders, including microcephaly, epileptic encephalopathy, and progressive neurodegeneration.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy | Loss-of-function mutations impair valyl-tRNA charging, reducing global protein synthesis and neuronal viability | PMID: 30580808, ClinVar |
| Progressive leukoencephalopathy with axonal spheroids | Missense variants disrupt enzyme activity and protein stability | PMID: 31585110, OMIM |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 12.5 | Medium |
| Liver | 18.3 | Medium |
| Kidney | 15.7 | Medium |
| Heart | 10.2 | Medium |
| Testis | 8.9 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK293 | 14.1 | High expression |
| HeLa | 11.3 | Moderate expression |
| SH-SY5Y | 9.8 | Neuronal cell line |
| HepG2 | 16.5 | Hepatocyte model |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1079G>A (p.Arg360Gln) | Missense | Rare | Reduced catalytic activity |
| c.1825C>T (p.Arg609Trp) | Missense | Rare | Impaired tRNA binding |
| c.2344C>T (p.Arg782*) | Nonsense | Rare | Loss of function, nonsense-mediated decay |
Mutation functional classification
Loss of Function (LOF)
Most pathogenic VARS1 mutations are loss-of-function, leading to reduced aminoacylation activity and protein synthesis deficits.
Gain of Function (GOF)
No gain-of-function mutations have been reported for VARS1.
Dominant Negative (DN)
Some missense variants may exert dominant-negative effects by interfering with dimerization or tRNA binding.
View complete mutation data：
Gene Ontology (GO)
| • valine-tRNA ligase activity | • ATP binding |
| • tRNA aminoacylation | • cytoplasm |
| • protein biosynthesis |
Pathways
• Aminoacyl-tRNA biosynthesis (KEGG: hsa00970)
• Cytoplasmic translation
Protein Summary
VARS1 is a 1264-amino-acid cytoplasmic enzyme that belongs to the class I aminoacyl-tRNA synthetase family. It contains a Rossmann fold catalytic domain, a tRNA anticodon-binding domain, and a C-terminal domain involved in dimerization. The enzyme requires ATP and magnesium for catalysis. Defects in VARS1 lead to impaired valine incorporation into proteins, particularly affecting rapidly dividing neurons during development.
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