Amino acid substitution types were extracted from the variants. For variants with multiple substitutions, all the substitutions were considered individually. Three substitution-type definitions were implemented: i) Categorical: Six substitution-type categories were defined based on the type of amino acid substitution regarding side chain size and polarity. 'Conservative' for amino acid substitutions where the size and polarity remained similar. 'Size' when size changed but polarity remained the same. 'Polar' and 'Charge' when the size remained similar but either the polarity or the actual charge, respectively, changed. And 'Polar size' and 'Charge size' as a combination of the aforementioned size and polarity changes. To define the changes, amino acids were grouped into four polarity groups and three size groups. Polarity groups included non-polar (alanine, glycine, isoleucine, leucine, proline, valine, methionine, phenylalanine), polar neutral (asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), polar acidic (glutamic acid, aspartic acid), and polar basic (arginine, histidine, lysine). Size groups were defined based on the relative side chain size previously defined by Epstein and included bulky (tryptophan, tyrosine, arginine, phenylalanine), intermediate (histidine, glutamic acid, glutamine, lysine, methionine, asparagine, leucine, isoleucine, proline), and small (cysteine, threonine, valine, alanine, glycine).