Phenotype-Specific Recalibration of MAVE Data Enables Repurposing of BAP1 Functional Assays for Kury-Isidor Syndrome

Purpose Multiplexed assays of variant effect (MAVEs) are transforming clinical variant interpretation. However, many genes are associated with more than one disease, making it unclear whether functional data generated in one disease context may be directly applicable to another. For example, germline BAP1 missense variants are associated with both BAP1 tumor predisposition syndrome (BAP1-TPDS) and Kury-Isidor syndrome (KURIS), a rare neurodevelopmental disorder. Here, we demonstrate how phenotype-specific calibration of BAP1 MAVE data enables disease-specific variant classification. Methods Saturation genome editing (SGE) data for BAP1 were recalibrated using either BAP1-TPDS- or KURIS-associated missense variants as pathogenic controls. Functional evidence strength was quantified using the Odds of Pathogenicity (OddsPath) framework and mapped to ACMG/AMP PS3/BS3 criteria. Recalibrated functional evidence was integrated with standard clinical criteria for variant classification. A workshop was developed to teach phenotype-specific MAVE recalibration to clinicians and variant curators and evaluated for educational impact. Results Phenotype-specific recalibration using BAP1-TPDS and KURIS controls yielded OddsPath values consistent with PS3_Strong evidence in both contexts. Application of KURIS-specific recalibration enabled the diagnosis of KURIS in an individual with a previously uncertain BAP1 missense variant. The educational workshop enabled quantitatively improved understanding in applying functional evidence. Conclusion Phenotype-specific recalibration enables appropriately calibrated reuse of MAVE datasets across distinct disease contexts, increasing the clinical utility of MAVE datasets and the interpretability of variants in pleiotropic genes. This framework expands the diagnostic utility of existing functional datasets without requiring new experimental assays.