Computational Prioritization of ABCA7 Missense Variants for Alzheimer’s Disease Risk Reclassification

• Sabrina Wang, Medical Diagnostics, University of Delaware

• Esther Biswas-Fiss, Medical and Molecular Sciences, University of Delaware
• Subhasis Biswas, Medical and Molecular Sciences, University of Delaware

Alzheimer’s Disease (AD) is the leading cause of dementia and currently has no cure. The ATP-binding cassette sub-family A member 7 (ABCA7) gene has been associated with increased disease risk in loss-of-function variants. Despite being a known risk factor, the vast majority of ABCA7 variants remain variants of uncertain significance (VUS), limiting genetic screening for AD. This study aims to predict which VUS are primary candidates for pathogenic reclassification using in silico tools. 

Over 400 missense variants were retrieved from ClinVar and scored using REVEL via dbNSFP.  To assess evolutionary conservation, ABCA7 and its ABCA1 and ABCA4 paralog sequences were downloaded from UniProt and imported to Jalview for multiple sequence analysis (MSA). Conserved residues across all three paralogs were recorded for further analysis. Residues conserved across all three paralogs were identified, and ABCA1/ABCA4 variants at those positions previously classified as likely pathogenic/pathogenic were used to support reclassification of the corresponding ABCA7 variants. Through this combined approach, 7 ABCA7 missense variants were identified as priority candidates for functional follow-up.

These findings provide a framework for systematic VUS prioritization in ABCA7, which may improve the efficiency of genetic screening efforts for AD risk. Future functional studies will be needed to validate predicted pathogenicity and support clinical reclassification of these high priority ABCA7 candidates.