missense

Missense mutation is a type of single-nucleotide variant in a protein-coding gene in which a base substitution changes one codon to encode a different amino acid. This contrasts with synonymous (silent) mutations that do not alter the amino acid, and nonsense mutations that create a premature stop codon.

Impact ranges from benign to detrimental; it depends on the nature of the amino acid substitution, the role of the affected residue, and its structural context. Conservative substitutions replace an amino acid with a similar one and often have milder effects; non-conservative substitutions can disrupt structure, stability, or function.

Examples include the sickle cell mutation, a Glu6Val substitution in beta-globin, and the BRAF V600E mutation, a well-known cancer-related missense change. Such substitutions can alter enzyme activity, binding interactions, or protein stability, and may contribute to disease or phenotypic variation.

Detection and interpretation involve sequencing to identify variants, followed by functional assays and computational predictions (such as SIFT, PolyPhen-2, and CADD). Evolutionary conservation across species also informs likelihood of functional importance.

Clinical relevance varies: many missense variants are associated with inherited diseases or predispositions, while others are common polymorphisms with no disease effect. Variants are typically classified as pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, or benign.

In population genetics, missense variants contribute to genetic diversity, and their frequencies aid interpretation of potential effects. Overall, missense mutations are a major category of coding-sequence variation with diverse effects, and their interpretation requires integrating biochemical, computational, and clinical data.