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Background  The reported prevalence of Alport syndrome varies from one in 5000 to one in 53,000 individuals. This study estimated the frequencies of predicted pathogenic  COL4A3–COL4A5  variants in sequencing databases of populations without known kidney disease.    Methods  Predicted pathogenic variants were identified using filtering steps based on the ACMG/AMP criteria, which considered collagen IV  α 3– α 5 position 1 Gly to be critical domains. The population frequencies of predicted pathogenic  COL4A3–COL4A5  variants were then determined per mean number of sequenced alleles. Population frequencies for compound heterozygous and digenic combinations were calculated from the results for heterozygous variants.    Results   COL4A3–COL4A5  variants resulting in position 1 Gly substitutions were confirmed to be associated with hematuria (for each,  P &lt;0.001). Predicted pathogenic  COL4A5  variants were found in at least one in 2320 individuals. p.(Gly624Asp) represented nearly half (16 of 33, 48%) of the variants in Europeans. Most  COL4A5  variants (54 of 59, 92%) had a biochemical feature that potentially mitigated the clinical effect. The predicted pathogenic heterozygous  COL4A3  and  COL4A4  variants affected one in 106 of the population, consistent with the finding of thin basement membrane nephropathy in normal donor kidney biopsy specimens. Predicted pathogenic compound heterozygous variants occurred in one in 88,866 individuals, and digenic variants in at least one in 44,793.    Conclusions  The population frequencies for Alport syndrome are suggested by the frequencies of predicted pathogenic  COL4A3–COL4A5  variants, but must be adjusted for the disease penetrance of individual variants and for the likelihood of already diagnosed disease and non-Gly substitutions. Disease penetrance may depend on other genetic and environmental factors

Prevalence Estimates of Predicted Pathogenic COL4A3–COL4A5 Variants in a Population Sequencing Database and Their Implications for Alport Syndrome