Understanding the molecular mechanisms that correlate pathologies with
missense mutations is of critical importance for disease risk
estimations and for devising personalized therapies. Thus, we have
performed a bioinformatic survey of ClinVar, a database of human genomic
variations, to find signals that can account for missense mutation
pathogenicity. Arginine resulted as the most frequently replaced amino
acids both in benign and pathogenic mutations. By adding the structural
dimension to this investigation to increase its resolution, we found
that arginine mutations occurring at the protein-DNA interface increase
pathogenicity 6.5 times with respect to benign variants. Glycine is the
second amino acid among all the pathological missense mutations.
Necessarily replaced by larger amino acids, glycine replacements perturb
the structural stability of proteins and, therefore, their functions,
being mostly located in buried protein moieties. Arginine and glycine
appear as representative of missense mutations causing respectively
changes in interaction processes and in protein structural features, the
two main molecular mechanisms of genome-induced pathologies.