Challenges in Classification of PKD1 Missense Variation in Autosomal Dominant Polycystic Kidney Disease

Autosomal Dominant Polycystic Kidney Disease is the most common monogenic kidney disease, largely caused by variants in the PKD1 gene. The study analyzed 389 missense variants in PKD1 reported as pathogenic or likely benign in ClinVar and PKDB databases. Using ACMG/AMP criteria, 346 out of 389 variants (89 percent) were reclassified as Variants of Unknown Significance. Among five computational prediction tools tested, REVEL achieved the highest sensitivity of 62 percent with specificity of 79 percent. AlphaMissense did not misclassify any variant, but many of its scores fell between pathogenic and benign thresholds. The findings demonstrate that the majority of PKD1 missense variants are classified as variants of unknown significance and commonly used computational tools with standard genome-wide thresholds are not reliable for distinguishing pathogenic from benign variants.