Genomic profiling reveals recurrent mutations in TP53, BAP1, and CDKN2A in sarcomatoid RCC, and NF2, SETD2, or ALK/NTRK fusions in unclassified RCC, indicating convergent pathways of dedifferentiation, chromatin remodeling, and cell-cycle dysregulation. Here, SETD2 is linked to renal cell carcinoma.