Such disease-causing variants generally display a lower frequency of being observed in the population due to selective pressures. Missense single nucleotide variants, which result in the substitution of a single amino acid residue at the protein level, are responsible for a large fraction of all currently known human genetic disorders 1, 2. Overall, our work suggests that many pathogenic mutations that act via DN and GOF mechanisms are likely being missed by current variant prioritisation strategies, but that there is considerable scope to improve computational predictions through consideration of molecular disease mechanisms. However, we do show that non-LOF mutations could potentially be identified by their tendency to cluster in three-dimensional space. We also find that nearly all computational variant effect predictors, even those based solely on sequence conservation, underperform on non-LOF mutations. We observe striking differences between recessive vs dominant, and LOF vs non-LOF mutations, with dominant, non-LOF disease mutations having much milder effects on protein structure, and DN mutations being highly enriched at protein interfaces. ![]() Here, we investigate the protein-level effects of pathogenic missense mutations associated with different molecular mechanisms. ![]() While there has been much focus on how mutations can disrupt protein structure and thus cause a loss of function (LOF), alternative mechanisms, specifically dominant-negative (DN) and gain-of-function (GOF) effects, are less understood. Taking protein structure into account has therefore provided great insight into the molecular mechanisms underlying human genetic disease. Most known pathogenic mutations occur in protein-coding regions of DNA and change the way proteins are made.
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