• SNP;
  • missense mutation;
  • protein structure;
  • disease;
  • modeling;
  • structural biology


Inherited disease susceptibility in humans is most commonly associated with single nucleotide polymorphisms (SNPs). The mechanisms by which this occurs are still poorly understood. We have analyzed the effect of a set of disease-causing missense mutations arising from SNPs, and a set of newly determined SNPs from the general population. Results of in vitro mutagenesis studies, together with the protein structural context of each mutation, are used to develop a model for assigning a mechanism of action of each mutation at the protein level. Ninety percent of the known disease-causing missense mutations examined fit this model, with the vast majority affecting protein stability, through a variety of energy related factors. In sharp contrast, over 70% of the population set are found to be neutral. The remaining 30% are potentially involved in polygenic disease. Hum Mutat 17:263–270, 2001. © 2001 Wiley-Liss, Inc.