SETD2 is a histone H3 lysine 36 trimethylase (H3K36me3); its loss in ccRCC leads to global H3K36me3 depletion accompanied by marked re-organization of the epigenome, particularly the repressive H3K27me3 mark deposited by polycomb repressive complex 2 (PRC2) and increased genomic accessibility accompanied by ectopic enhancer activation [8,9]. The gene discussed is SETD2; the disease is nonpapillary renal cell carcinoma.