Val158Met

Val158Met (also referred to as rs4680) is a single‑nucleotide polymorphism in the catechol‑O‑methyltransferase (COMT) gene that results in a substitution of valine (Val) with methionine (Met) at codon 158 of the membrane‑bound COMT isoform (or codon 108 of the soluble isoform). The variant alters the stability of the COMT enzyme; the Met allele produces a thermally less stable protein with approximately one‑quarter the activity of the Val form. Consequently, individuals carrying the Met allele exhibit higher synaptic dopamine concentrations, particularly in the prefrontal cortex, where COMT is a primary mechanism for dopamine catabolism.

The Val158Met polymorphism has been studied extensively in relation to neuropsychiatric traits. Met carriers are frequently associated with enhanced performance on tasks of executive function and working memory, whereas Val homozygotes may show greater susceptibility to stress‑induced cognitive deficits. Associations have also been reported with anxiety, depressive symptoms, pain perception, and risk for substance use disorders, although effect sizes are modest and findings sometimes contradictory. In pharmacogenomics, COMT genotype can influence response to dopaminergic agents and the side‑effect profile of antipsychotics.

The allele frequencies of Val and Met vary across populations, with the Met allele being more common in East Asian groups and less prevalent in African populations. Because COMT activity modulates catecholamine signaling, Val158Met remains a focal point in research on gene‑environment interactions, neurodevelopmental disorders, and personalized medicine.