Abstract: SA-PO0613
Population Frequencies of Predicted Pathogenic Variants in Common Genes Associated with Kidney Failure
Session Information
- Monogenic Kidney Diseases: Tubular and Other
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases
Authors
- Savige, Judith A., The University of Melbourne Faculty of Medicine Dentistry and Health Sciences, Melbourne, Victoria, Australia
- Huang, Mary, The University of Melbourne Faculty of Medicine Dentistry and Health Sciences, Melbourne, Victoria, Australia
- Varughese, Santosh, The University of Melbourne Faculty of Medicine Dentistry and Health Sciences, Melbourne, Victoria, Australia
Background
Genetic disease accounts for at least 10% of people with end-stage kidney failure but is often unrecognised. One reason to suspect a particular genetic disease is that it is common. However the reported population frequencies are often underestimates because they depend on a diagnosis being made. This study calculated the population frequencies of predicted pathogenic variants in the common genes associated with end-stage kidney failure in the gnomAD database.
Methods
Variants in common genetic causes of kidney failure (COL4A3-COL4A5, PKD1, PKD2, MUC1, UMOD, HNF1B, GLA, CLCN5) were downloaded from gnomAD v.2.1 or 4, annotated with ANNOVAR and predicted pathogenic variants identified from structural and copy number loss of function variants; null variants; and missense changes that were damaging in three computational tools (PP2, SIFT, MT) and affected a conserved residue. The population frequency was calculated from the sum of predicted pathogenic variants in gnomAD and compared with the population frequency derived from gnomAD variants assessed as Pathogenic, Likely Pathogenic or Conflicting (combined with a VUS) in ClinVar. Calculations presumed that predicted pathogenic variants occurred throughout the gene and each person had only one.
Results
The commonest genes associated with kidney failure were COL4A3 and COL4A4 but their risk of kidney failure was low. The commonest genetic causes of kidney failure according to our assessment were PKD1 (one in 420), COL4A5 (one in 622), CLCN5 (one in 723), PKD2 (one in 922), UMOD (one in 2053, including missense variants throughout the gene), HNF1B (one in 1988) and GLA (one in 3225). Scores were not available for MUC1 or the CAKUT genes. Results were generally much lower using ClinVar which does not include assessments of all gnomAD variants.
Conclusion
These results suggest that one in 151 people have a predicted pathogenic variant in a gene associated with kidney failure. However some variants have incomplete penetrance and are not always associated with kidney failure. These population frequencies will become more accurate with further refinement of the computational tools and with greater understanding of the disease mechanisms.
Funding
- Private Foundation Support