SNPs, protein structure, and disease

Hum Mutat. 2001 Apr;17(4):263-70. doi: 10.1002/humu.22.


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.

MeSH terms

  • Allosteric Regulation
  • Catalysis
  • Computational Biology
  • Databases as Topic
  • Disulfides / metabolism
  • Enzyme Stability / genetics
  • Genetic Diseases, Inborn / genetics*
  • Genetic Predisposition to Disease
  • Humans
  • Hydrogen Bonding
  • Ligands
  • Models, Molecular
  • Multifactorial Inheritance / genetics
  • Mutation, Missense / genetics*
  • Polymorphism, Single Nucleotide / genetics*
  • Protein Binding
  • Protein Conformation
  • Protein Processing, Post-Translational
  • Proteins / chemistry*
  • Proteins / genetics
  • Proteins / metabolism*
  • Static Electricity
  • Structure-Activity Relationship
  • Thermodynamics


  • Disulfides
  • Ligands
  • Proteins