Genotype–Phenotype Correlations of Monoallelic PFIC Variants in Pediatric Liver Disease: A Multicenter Retrospective Cohort Study

Progressive familial intrahepatic cholestasis (PFIC) is classically caused by biallelic pathogenic variants, yet monoallelic variants of uncertain significance (VUS) in PFIC‐associated genes are increasingly identified in children with cholestasis, creating diagnostic uncertainty. We conducted a multicenter cohort study of children with liver disease and/or cholestasis harboring monoallelic VUS in ATP8B1 , ABCB11 , ABCB4 , TJP2 , or NR1H4 . Clinical and longitudinal data were analyzed, and variant frequencies were compared with population data from gnomAD. Twenty‐six children with 37 monoallelic PFIC‐gene VUS met inclusion criteria, and multigenic variant burden was common (73.1%). PFIC‐like biochemical patterns were observed in 42.3% but were frequently transient, and no patient met criteria for monogenic PFIC on longitudinal follow‐up. Severe liver outcomes, including transplantation in two patients, occurred in a subset of patients with ABCB4 and/or ATP8B1 VUS and multigenic burden, along with competing clinical factors. Among 22 variants with population data, 11 (50%) demonstrated significant enrichment after multiple‐testing correction, most commonly involving ABCB4 . These findings suggest that monoallelic PFIC‐associated variants currently classified as VUS are unlikely to represent monogenic disease drivers in isolation and may instead contribute within multigenic or susceptibility‐based contexts. Population‐level enrichment, particularly involving ABCB4 , further supports careful phenotype‐anchored, longitudinal interpretation in pediatric liver disease.