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. Copyright 2001 Wiley-Liss, Inc.