Large collections of human genomic sequencing data enable us to study sequence variant architecture as well as rare phenomena in the general population. The Genome Aggregation Database (gnomAD) is the most widely used open-access variant database with aggregated data from 200,000 individuals. Investigating presumably unaffected individuals in gnomAD with a variant associated with disease provides an opportunity to identify mechanisms of incomplete penetrance and increase understanding of variant effects. Focusing on predicted loss of function (pLoF) variants (nonsense, frameshift, and essential splice site variants) associated with severe, highly penetrant, pediatric phenotypes, and access to over 76,000 genomes allowed us to study hundreds of these cases. Our studies have increased our understanding of pathogenic variants' rescue and error modes and informed us on properties protecting against disease. A better understanding of variant penetrance improves our ability to interpret the human genome, and defining underlying mechanisms can highlight potential suitable therapeutic targets in the future.