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Prostate 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 the ELAC2 gene, which encodes a dually localised nuclear and mitochondrial RNA processing enzyme, into the mouse Elac2 gene as well as to generate a prostate‐specific knockout of Elac2. These mutations caused enlargement and inflammation of the prostate and nodule formation. The Elac2 variant or knockout mice on the background of the transgenic adenocarcinoma of the mouse prostate (TRAMP) model show that Elac2 mutation 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 the ELAC2 variant is a predisposing factor for prostate cancer and identify changes that underlie the pathogenesis of this cancer. Synopsis: Polymorphisms in ELAC2 have been correlated with prostate cancer, but a definitive link has been lacking. Introducing a common prostate‐susceptibility variant into mice increases inflammation, perturbs the production of non‐coding RNAs, and rewires cellular signaling to exacerbate tumorigenesis. Mice carrying a point mutation equivalent to the human Ala541Thr variant in ELAC2 have inflammation of the prostate and nodule formation.In the presence of a secondary oncogenic stimulus, the ELAC2 variant exacerbates prostate cancer onset and progression.The ELAC2 polymorphism increases cell proliferation, migration, immunometabolic and inflammatory pathways, such as MAPK activation.Production of noncoding RNAs, including tRNAs and miRNAs, is perturbed, leading to defects in protein homeostasis and OXPHOS.ELAC2 interacts with NONO/SFPQ, and the ELAC2 polymorphism reduces this interaction, providing an additional link between altered gene expression in the nucleus and mitochondria. [ABSTRACT FROM AUTHOR]