VARS2 encodes a mitochondrial valyl-tRNA synthetase that catalyzes the two-step aminoacylation of valine to tRNA(Val), with valine first activated by ATP to form Val-AMP before transfer to the acceptor end of tRNA(Val) 1. This enzyme is essential for mitochondrial protein synthesis and oxidative phosphorylation. Pathogenic VARS2 mutations cause combined oxidative phosphorylation deficiency manifesting as early-onset mitochondrial encephalomyopathies. A homozygous missense mutation was identified in a patient with microcephaly and epilepsy exhibiting isolated respiratory chain complex I deficiency 1. Affected individuals show decreased VARS2 protein levels and reduced valyl-tRNA abundance; wild-type transcript expression in patient fibroblasts rescued mitochondrial respiratory function 1. Beyond monogenic disease, VARS2 variants associate with complex diseases. VARS2-SFTA2 polymorphisms correlate with chr6 hepatitis B risk in Asian populations 2. Genome-wide Mendelian randomization identified VARS2 methylation as causally associated with lung cancer risk 3. Additionally, VARS2 emerged as a critical mediator of RIG-I-induced endothelial dysfunction through interferon-stimulated gene regulation 4. DNA methylation at VARS2 showed significant association with bipolar disorder polygenic risk in high familial-risk individuals 5. These findings establish VARS2 as both a critical mitochondrial enzyme and a pleiotropic gene influencing cancer, viral response, and psychiatric phenotypes.