Protein-truncating variants (PTVs), which often inactivate proteins, provide direct insight into human biology and disease mechanisms26,27. Identifying PTVs that are protective against disease can also offer direct human validation of potential therapeutic targets5,28. Among 287,917 participants of any ancestry, we observed that 96% of 18,762 studied genes had at least one heterozygous PTV carrier, 46% had at least one compound heterozygous or homozygous/hemizygous PTV carrier, and 20% had at least one homozygous/hemizygous PTV carrier (Fig. 1a). Only 884 genes (4.7%) had PTVs with a MAF > 0.5% (Fig. 1a), illustrating the power of exome sequencing to detect this important form of variation. Although some have been implicated in human diseases, most common PTVs occur in genes that are less relevant to disease, such as olfactory receptor genes29. Focusing on rarer PTVs (MAF < 1%), we observed that 95% of genes had at least one heterozygous PTV carrier, 42% had at least one compound heterozygous or homozygous/hemizygous PTV carrier, and only 15% had at least one homozygous/hemizygous PTV carrier (Extended Data Fig. 2a).
