SummaryThere are >200 types of protein posttranslational modifications (PTMs) described in eukaryotes, each with unique proteome coverage and functions. We hypothesized that some genetic diseases may be caused by the removal of a specific type of PTMs by genomic variants and the consequent deregulation of particular functions. We collected >320,000 human PTMs representing 59 types and crossed them with >4M nonsynonymous DNA variants annotated with predicted pathogenicity and disease associations. We report >1.74M PTM-variant co-occurrences that an enrichment analysis distributed into 215 pairwise associations between 18 PTM types and 148 genetic diseases. Of them, 42% were not previously described. Removal of lysine acetylation exerts the most pronounced effect, and less studied PTM types such as S-glutathionylation or S-nitrosylation show relevance. Using pathogenicity predictions, we identified PTM sites that may produce particular diseases if prevented. Our results provide evidence of a substantial impact of PTM-specific removal on the pathogenesis of genetic diseases and phenotypes.