loss-of-function (LoF) alleles are known to cause a rare autosomal dominant disorder-posterior polymorphous corneal dystrophy type 3 (PPCD3). To date, 50 pathogenic LoF variants have been identified as disease-causing and familial studies have indicated that the PPCD3 phenotype is penetrant in approximately 95% of carriers. In this study, we interrogated in-house exomes ( = 3616) and genomes ( = 88) for the presence of putative heterozygous LoF variants in . Next, we performed detailed phenotyping in a father and his son who carried a novel LoF c.1279C>T; p.(Glu427*) variant in (NM_030751.6) absent from the gnomAD v.2.1.1 dataset. Ocular examination of the two subjects did not show any abnormalities characteristic of PPCD3. GnomAD ( = 141,456 subjects) was also interrogated for LoF variants, notably 8 distinct heterozygous changes presumed to lead to haploinsufficiency, not reported to be associated with PPCD3, have been identified. The NM_030751.6 transcript has a pLI score ≥ 0.99, indicating extreme intolerance to haploinsufficiency. In conclusion, LoF variants are present in a general population at an extremely low frequency. As PPCD3 can be asymptomatic, the true penetrance of LoF variants remains currently unknown but is likely to be lower than estimated by the familial led approaches adopted to date.