LAUSR

Significance Increasing numbers of human genome population sequences provide new detail on the genetic variability of the human proteome. It is possible to identify proteins that are depleted in genetic variation, and this approach can now be extended to the identification of 3D features and structures that are uniquely intolerant to variation. We speculated that 3D features that are intolerant to variation correspond to privileged functional domains of the protein. We approached this question with sequence data nearly 140,000 individuals with modeling of >8,500 protein structures. In keeping with the hypothesis, structural predictions correlated with experimental functional readouts. We believe that information derived from human variation complements other metrics at the structural level and can serve to inform drug development. Sequence variation data of the human proteome can be used to analyze 3D protein structures to derive functional insights. We used genetic variant data from nearly 140,000 individuals to analyze 3D positional conservation in 4,715 proteins and 3,951 homology models using 860,292 missense and 465,886 synonymous variants. Sixty percent of protein structures harbor at least one intolerant 3D site as defined by significant depletion of observed over expected missense variation. Structural intolerance data correlated with deep mutational scanning functional readouts for PPARG, MAPK1/ERK2, UBE2I, SUMO1, PTEN, CALM1, CALM2, and TPK1 and with shallow mutagenesis data for 1,026 proteins. The 3D structural intolerance analysis revealed different features for ligand binding pockets and orthosteric and allosteric sites. Large-scale data on human genetic variation support a definition of functional 3D sites proteome-wide.