AbstractNext generation sequencing technologies are providing increasing amounts of sequencing data, paving the way for improvements in clinical genetics and precision medicine. The interpretation of the observed genomic variants in the light of their phenotypic effects is thus emerging as a crucial task to solve in order to advance our understanding of how exomic variants affect proteins and how the proteins’ functional changes affect human health. Since the experimental evaluation of the effects of every observed variant is unfeasible, Bioinformatics methods are being developed to address this challenge in-silico, by predicting the impact of millions of variants, thus providing insight into the deleteriousness landscape of entire proteomes. Here we show the feasibility of this approach by using the recently developed DEOGEN2 variant-effect predictor to perform the largest in-silico mutagenesis scan to date. We computed the deleteriousness score of 170 million variants over 15000 human proteins and we analysed the results, investigating how the predicted deleteriousness landscape of the proteins relates to known functionally and structurally relevant protein regions and biophysical properties. Moreover, we qualitatively validated our results by comparing them with two mutagenesis studies targeting two specific proteins, showing the consistency of DEOGEN2 predictions with respect to experimental data.