Gibson J, Fieldhouse R, Chan MMY, et al. - The frequencies of predicted pathogenic COL4A3–COL4A5 variants indicated the population frequencies for Alport syndrome, however, should necessarily be adjusted for the disease penetrance of individual variants as well as for the probability of already diagnosed disease and non-Gly substitutions. Disease penetrance may rely on other genetic and environmental factors.

• The population frequencies of Alport syndrome differ hugely in different reports.

• A population sequencing database of people not known to have kidney disease was examined.

• Filtering steps were used based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria, which considered collagen IV α3–α5 position 1 Gly to be critical domains.

• COL4A3–COL4A5 variants causing position 1 Gly substitutions were corroborated to be linked with hematuria (for each, P<0.001).

• In at least one in 2320 persons, predicted pathogenic COL4A5 variants were present.

• Heterozygous COL4A3 or COL4A4 variants impacted one in 106; compound heterozygous COL4A3 or COL4A4 variants affected one in 88,866.

• The observed frequency of predicted pathogenic COL4A3–COL4A5 variants was high.