Common single-amino acid variations of proteins are traditionally regarded as functionally neutral polymorphisms because these substitutions are mostly located outside functionally relevant surfaces. In this study, we present an example of a functionally relevant coding sequence variation, which, as we show here, confers risk for large artery atherosclerotic stroke. The single-residue variation M1(A213V) in serpin family A member 1 (
SERPINA1) [encoding alpha-1 antitrypsin (AAT)] is situated outside the protease-reactive inhibitory loop and is found in a β-turn on the protein surface. We show that the Ala-to-Val exchange in the gate region of AAT alters its functional dynamics toward neutrophil elastase in the presence of complex lipid-containing plasma and also affects the overall structural flexibility of the protein.