This study investigates the impact of common germline variants in the EXO5 gene, which plays a key role in DNA repair and cancer susceptibility. Using a combination of genomic analysis, deep learning variant prediction, and molecular dynamics simulations, we identified five common EXO5 haplotypes and analyzed their effects on protein structure and cancer outcomes. Notably, the L151P variant caused significant structural changes, potentially impairing EXO5 function and nuclear localization. TCGA data linked L151P to shorter progression-free survival in prostate and pancreatic cancers and increased genomic instability. Our study underscores the power of integrative approaches in understanding variant effects on disease.