EIF2B2 encodes the beta subunit of eukaryotic translation initiation factor 2B (eIF2B), a guanine nucleotide exchange factor (GEF) that catalyzes GDP-to-GTP exchange on eIF2 gamma to enable translation initiation 123. When eIF2 alpha is phosphorylated during cellular stress, EIF2B2-containing eIF2B becomes inhibited, suppressing global translation and allowing stress-responsive gene expression 13. Mutations in EIF2B2 cause leukoencephalopathy with vanishing white matter (VWM), an autosomal recessive neurological disease characterized by progressive white matter loss and cystic degeneration 45. VWM manifests with variable onset (infantile to adult) and is triggered by physical stress or infection 6. Mechanistically, EIF2B2 mutations impair the integrated stress response, causing prolonged translational hyperrepression during acute stress and delayed recovery of stress-induced gene expression, leading to white matter vulnerability 7. Adult genetic leukoencephalopathy studies show EIF2B mutations account for approximately half of astrocytopathy cases 5. Additionally, EIF2B2 variants have been identified as potential genetic risk factors in premature ovarian insufficiency 89 and as CAD/myocardial infarction risk genes in immune-related contexts 10, suggesting pleiotropic functions beyond translation initiation.