Collectively, our data reveal a shift in DCLK1 AP model choice during ccRCC tumorigenesis, emphasize the tumorigenic contribution of DCLK1-L variants in ccRCC stemness and aggressiveness, identify a hypoxia-HIF2α-PLOD2 axis that activates β-catenin to preferentially drive α-promoter activation and DCLK1-L variants production, and propose DCLK1-L as a potential therapeutic target in hypoxic, PLOD2-rich ccRCCs. Here, DCLK1 is linked to nonpapillary renal cell carcinoma.