To validate the functional contribution of m6A hypermethylated transcripts to cell survival and proliferation in ccRCC, we generated isogenic METTL3 knockout (KO) cells in both a SETD2 WT and SETD2 KO ccRCC cell line context and demonstrate that METTL3 inactivation, or treatment with the METTL3 inhibitor STM2457, preferentially reduced cell growth and colony forming potential, increased apoptosis, and downregulated key genes in pathways that promote metabolic reprogramming in a SETD2 mutant ccRCC cell line. Here, SETD2 is linked to nonpapillary renal cell carcinoma.