Addendum: The mutational constraint spectrum quantified from variation in 141,456 humans

Databases of human population genetic variation, such as the Genome Aggregation Database (gnomAD), are generally expected to be depleted for variation with severe effects on health. As such, it is expected that genes that carry highly disruptive changes, predicted (p)LoF variants, in these databases are less likely to be responsible for severe human disease. However, the precise relationship between pLoF tolerance and human disease causation is not well-characterized.