For rare variants, it will nearly always be the case that the functional effect is due to the variant itself. This is because of the choice of candidate gene, the assessment of the effect of the variant on the function of the gene product, and the extremely low probability of finding two rare variants with comparable functional effects in closely linked genes. Most rare variants are likely to be missense variants, and their functional effects may be expected to arise mostly from amino acid changes that affect protein–protein interactions and that can thus have mildly dominant or dominant-negative effects. Variants in promoter regions may also be relevant, through dominant effects on gene expression.
