In the present study, we sought to gain a better understanding of epigenetic ITH at the level of methylation within ccRCC by integrating 5mC heterogeneity with genetic and pathologic data, determine the specific influence of SETD2 mutations on ITH given its role in regulating DNA methylation, and apply evolutionary principles to discover novel epigenetic cancer driver events. The gene discussed is SETD2; the disease is nonpapillary renal cell carcinoma.