AbstractProstate cancer is the most commonly diagnosed malignancy and the third leading cause of cancer deaths. GWAS have identified variants associated with prostate cancer susceptibility; however, mechanistic and functional validation of these mutations is lacking. We used CRISPR‐Cas9 genome editing to introduce a missense variant identified in theELAC2gene, which encodes a dually localised nuclear and mitochondrial RNA processing enzyme, into the mouseElac2gene as well as to generate a prostate‐specific knockout ofElac2. These mutations caused enlargement and inflammation of the prostate and nodule formation. TheElac2variant or knockout mice on the background of the transgenic adenocarcinoma of the mouse prostate (TRAMP) model show thatElac2mutation with a secondary genetic insult exacerbated the onset and progression of prostate cancer. Multiomic profiling revealed defects in energy metabolism that activated proinflammatory and tumorigenic pathways as a consequence of impaired noncoding RNA processing and reduced protein synthesis. Our physiologically relevant models show that theELAC2variant is a predisposing factor for prostate cancer and identify changes that underlie the pathogenesis of this cancer.