Collectively, we have (i) validated earlier findings of deleterious variants present in the human genome; (ii) discovered a set of genes having validated prevalent inactivating alleles in the population; (iii) identified CYP2D6 as a putative target for LOH therapy; and (iv) demonstrated increased cytotoxicity of talazoparib in hepatocellular cancer cell models and organoids. Here, CYP2D6 is linked to hepatocellular carcinoma.