The variability in the fractional contribution of nonsense, splice-site, and frameshift indels to the mutational load across genes is intriguing. Although for autosomal-recessive genes this variability may not affect the outcome at the protein level (as most of these variants are expected to result in null alleles), the story is quite different for autosomal-dominant genes. The latter exert their effect via haploinsufficieny or a gain-of-function/dominant-negative mode of action, and the specific type of mutation might be crucial. LoF variants in genes known to have a dominant-negative/gain-of-function mechanism of action are not traditionally predicted to be pathogenic for a dominant disease. However, this caveat ignores the position-dependent effect of these variants on nonsense-mediated mRNA decay (NMD).47 For example, truncating pathogenic variants in DIAPH1 are linked to two different phenotypes: (1) autosomal-recessive seizures, cortical blindness, and microcephaly syndrome (MIM: 616632) due to null alleles through NMD and (2) autosomal-dominant DFNA1 hearing loss with thrombocytopenia due to gain-of-function truncating variants (that escape NMD) in the C-terminal DAD domain, which disrupt the autoinhibitory activity of the DAD and renders the protein constitutively active.48, 49 SOX10 and PTPRQ are other examples where the impact of a LoF variant is position dependent.50, 51