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.

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.

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.

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

据报道，Alport 综合征的患病率从 5000 分之一到 53,000 分之一不等。这项研究估计了在没有已知肾脏疾病的人群的测序数据库中预测的致病性COL4A3–COL4A5变异的频率。

使用基于 ACMG/AMP 标准的过滤步骤确定预测的致病变异，该标准认为胶原蛋白 IV α 3– α 5 位置 1 Gly 是关键域。然后根据测序等位基因的平均数量确定预测的致病性COL4A3–COL4A5变体的群体频率。复合杂合子和双基因组合的群体频率是根据杂合子变体的结果计算的。

导致位置 1 Gly 取代的COL4A3–COL4A5变体被证实与血尿相关（对于每个，P <0.001）。在 2320 人中至少有一个人发现了预测的致病性COL4A5变异。p.(Gly624Asp) 占欧洲人变异的近一半（33 个中的 16 个，占 48%）。大多数COL4A5变体（59 个中的 54 个，92%）具有可能减轻临床效果的生化特征。预测的致病性杂合子COL4A3和COL4A4变异影响了 106 分之一的人群，这与正常供体肾活检标本中薄基底膜肾病的发现一致。预测的致病复合杂合变异在 88,866 人中有 1 人出现，双基因变异至少在 44,793 人中有 1 人出现。

Alport 综合征的人群频率由预测的致病性COL4A3–COL4A5变异的频率建议，但必须针对个体变异的疾病外显率以及已诊断疾病和非 Gly 替代的可能性进行调整。疾病外显率可能取决于其他遗传和环境因素