In ccRCC pathogenesis, ~10–20% of tumors acquire SETD2 mutation on the second intact allele (or more rarely acquire mutations on both alleles), resulting in biallelic loss of SETD2 and H3K36me3 depletion (Duns et al., 2010; Dalgliesh et al., 2010; Walton et al., 2023). The gene discussed is SETD2; the disease is nonpapillary renal cell carcinoma.