Autosomal Dominant Polycystic Kidney Disease (ADPKD) represents the most common monogenic cause of kidney failure. While identifying genetic variants predicts disease progression, characterization of recently described ADPKD-like variants is limited. We explored disease progression and genetic spectrum of genetically-confirmed ADPKD families with PKD1 and non-PKD1 variants.In this observational study, we evaluated the clinical (ADPKD-related complications, estimated glomerular filtration rate (eGFR) decline, and progression to kidney failure), radiological (height-adjusted total kidney volume (ht-TKV)), and genetic characteristics of ADPKD families referred to the Irish Kidney Gene Project. Logistic regression and Kaplan-Meier analyses examined relationships between genetic variants and disease progression.Genomic sequencing was performed on 261 ADPKD families, and 75.8% (198/261 families, comprising 391 individuals) were identified to harbor pathogenic/likely pathogenic variants; 74.2% (147/198) PKD1 families and 23.2% (46/198) non-PKD1 families, which include PKD2 (n = 29 families), IFT140 variants (n = 4), ALG5, DNAJB11 and NEK8 (n = 3 each), ALG8 and ALG9 variants (n = 2 each). The remaining 2.6% (5/198) accounted for non-ADPKD variants. Compared to PKD1, non-PKD1 families were characterized by a milder phenotype; milder eGFR decline (- 1.4 mL/min/1.73m2/year vs. - 3.2; p