Critically, we note that LoF-intolerant genes include virtually all known severe haploinsufficient human disease genes (Figure 3b), but that 72% of LoF-intolerant genes have not yet been assigned a human disease phenotype despite clear evidence for extreme selective constraint (Supplementary Information Table 13). We note that this extreme constraint does not necessarily reflect a lethal disease or status as a disease gene (e.g. BRCA1 has a pLI of 0), but is likely to point to genes where heterozygous loss of function confers some non-trivial survival or reproductive disadvantage.
