%A Lu,Hui-Chun %A Chung,Sun Sook %A Fornili,Arianna %A Fraternali,Franca %D 2015 %J Frontiers in Molecular Biosciences %C %F %G English %K Non-synonymous SNPs,Protein Disorder,Order-Disorder Propensity,Disease-related Mutations,protein flexibility %Q %R 10.3389/fmolb.2015.00047 %W %L %M %P %7 %8 2015-August-12 %9 Perspective %+ Prof Franca Fraternali,King's College London,Randall Division of Cellular and Molecular Biophysics,New Hunt's House,Guy's Campus,King's College London,London,SE1 1UL,United Kingdom,f.fraternali@ucl.ac.uk %# %! Protein disorder and disease %* %< %T Anatomy of protein disorder, flexibility and disease-related mutations %U https://www.frontiersin.org/articles/10.3389/fmolb.2015.00047 %V 2 %0 JOURNAL ARTICLE %@ 2296-889X %X Integration of protein structural information with human genetic variation and pathogenic mutations is essential to understand molecular mechanisms associated with the effects of polymorphisms on protein interactions and cellular processes. We investigate occurrences of non-synonymous SNPs in ordered and disordered protein regions by systematic mapping of common variants and disease-related SNPs onto these regions. We show that common variants accumulate in disordered regions; conversely pathogenic variants are significantly depleted in disordered regions. These different occurrences of pathogenic and common SNPs can be attributed to a negative selection on random mutations in structurally highly constrained regions. New approaches in the study of quantitative effects of pathogenic-related mutations should effectively account for all the possible contexts and relative functional constraints in which the sequence variation occurs.