Next Generation Protein Structure Predictions and Genetic Variant Interpretation

J Mol Biol. 2021 Oct 1;433(20):167180. doi: 10.1016/j.jmb.2021.167180. Epub 2021 Aug 4.


The need to make sense of the thousands of genetic variants uncovered every day in terms of pathology or biological mechanism is acute. Many insights into how genetic changes impact protein function can be gleaned if three-dimensional structures of the associated proteins are available. The availability of a highly accurate method of predicting structures from amino acid sequences (e.g. Alphafold2) is thus potentially a great boost to those wanting to understand genetic changes. In this paper we discuss the current state of protein structures known for the human and other proteomes and how Alphafold2 might impact on variant interpretation efforts. For the human proteome in particular, the state of the available structural data suggests that the impact on variant interpretation might be less than anticipated. We also discuss additional efforts in structure prediction that could further aid the understanding of genetic variants.

Keywords: Alphafold; genetic variants; prediction; protein function; protein structure.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Genetic Variation
  • Genomics / methods
  • Humans
  • Models, Molecular
  • Protein Conformation
  • Proteins / chemistry*
  • Proteins / genetics*
  • Proteome / chemistry
  • Proteome / genetics


  • Proteins
  • Proteome