rs4680

rs4680, also known as Val158Met, is a missense single nucleotide polymorphism in the COMT gene, located on chromosome 22q11.21. The G to A substitution changes the amino acid at position 158 from valine (Val) to methionine (Met) in the enzyme catechol-O-methyltransferase (COMT). The Met allele reduces the catalytic activity of COMT and lowers the enzyme’s thermal stability compared with the Val allele, leading to higher synaptic dopamine levels in brain regions where COMT plays a major role in degradation, notably the prefrontal cortex.

Functional implications: In the prefrontal cortex, where dopamine transporter–mediated reuptake is relatively limited, COMT activity significantly influences dopamine availability and signaling. This can affect aspects of executive function and working memory, particularly under high cognitive load. The relationship between rs4680 and cognitive performance or emotion processing is complex and has yielded mixed results across studies.

Clinical and psychiatric associations: rs4680 has been investigated for links to pain sensitivity, stress responses, personality traits, and various psychiatric conditions, including schizophrenia, bipolar disorder, and ADHD. Overall, findings are variable and effect sizes are small, with no clear, consistent risk prediction from this single polymorphism.

Pharmacogenomics: The variant may modulate response to dopaminergic therapies and certain medications, such as L-DOPA in Parkinson’s disease and some antidepressants or analgesics. However, evidence for clinically meaningful guidance based on rs4680 remains inconclusive and many effects are context- and environment-dependent.

Population genetics: Allele frequencies differ across populations, with the Met allele being relatively common in many ethnic groups. The functional impact of rs4680 is often discussed in conjunction with other genetic and environmental factors.