Together, our results demonstrate that (1) ITH is not restricted to genomic events, but rather is pervasive in the transcriptome, microenvironment, and immune compartment of ccRCC tumors, and (2) correlates with specific somatic events at the level of individual patients (i.e., PBRM1 and SETD2 mutations, HLA LOH and CDKN2A/B loss). Here, SETD2 is linked to nonpapillary renal cell carcinoma.