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 α3-α5 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<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.