Can Predicted Protein 3D Structures Provide Reliable Insights into whether Missense Variants Are Disease Associated?

Knowledge of protein structure can be used to predict the phenotypic consequence of a missense variant. Since structural coverage of the human proteome can be roughly tripled to over 50% of the residues if homology-predicted structures are included in addition to experimentally determined coordinates, it is important to assess the reliability of using predicted models when analyzing missense variants. Accordingly, we assess whether a missense variant is structurally damaging by using experimental and predicted structures. We considered 606 experimental structures and show that 40% of the 1965 disease-associated missense variants analyzed have a structurally damaging change in the mutant structure. Only 11% of…

• WT
  Wellcome Trust

  Award: 104955/Z/14/Z
• KA
  King Abdulaziz City for Science and Technology
• BA
  Biotechnology and Biological Sciences Research Council

  Awards: BB/M011526/1, BB/P011705/1, BB/P011705/1