Compensated pathogenic variants in coagulation factors VIII and IX present complex mapping between molecular impact and hemophilia severity.

Compensated pathogenic deviations (CPDs) are sequence variants that are pathogenic in humans but neutral in other species. In recent years, our molecular understanding of CPDs has advanced substantially. For example, it is known that their impact on human proteins is generally milder than that of average pathogenic mutations and that their impact is suppressed in non-human carriers by compensatory mutations. However, prior studies have ignored the evolutionarily relevant relationship between molecular impact and organismal phenotype. Here, we explore this topic using CPDs from FVIII and FIX and data concerning carriers' hemophilia severity. We find that, regardless of their molecular impact, these mutations can be associated with either mild or severe disease phenotypes. Only a weak relationship is found between protein stability changes and severity. We also characterize the population variability of hemostasis proteins, which constitute the genetic background of FVIII and FIX, using data from the 1000 Genome project. We observe that genetic background can vary substantially between individuals in terms of both the amount and nature of genetic variants. Finally, we discuss how these results highlight the need to include new terms in present models of protein evolution to explain the origin of CPDs.