The effect of a variant on an organism is always multifaceted and can be considered from multiple perspectives-biochemical, medical, or evolutionary. However, the relationship between the effects of amino acid substitution on protein activity, human health, and an individual's evolutionary fitness is not trivial. We uncover that the general Lithuanian population is characterized by a "mirror reflection" of the de novo variant fitness effect, confirming the theory of neutrality. Meanwhile, in the group of individuals with intellectual disability, compared with the reference exome de novo variants significantly changed the composition of the amino acid. Therefore, it predicts that, both in terms of the number of amino acids and changes in their relative fitness, the structure of the proteins encoded by the studied amino acids undergo significant changes following the de novo variant, leading to possible changes in protein function associated with phenotypic traits. These results suggest that the analysis of relative fitness of exome sequences with de novo variants can predict the future phenotype. Therefore even in those cases, then only a few of all functional prediction analysis tools predict a variant as damaging, the negative relative fitness or even adaptability of the genome variant should be carefully evaluated considering both its direct function and the global background of the possible disease-associated mechanism regardless of the phenotype being studied.
