Background: Unclassified renal cell carcinoma (uRCC) constitutes a large portion of aggressive non-clear cell RCC with limited response to standard therapy. Clinicopathologic parameters or biomarkers to stratify this heterogeneous group of tumors are currently lacking. In a recently reported analysis of 62 high-grade primary uRCC [“discovery cohort (DC)”], we identified distinct molecular subsets. We aimed to validate this molecular schema in an independent clinical cohort and further delineate the clinicopathologic and molecular features that may refine prognostication and management. Methods: All cases was reviewed by experienced GU pathologists based on the current WHO criteria. Primary (n = 54) or metastatic (n = 21) tumor samples from 75 uRCC patients [“validation cohort (VC)”] were analyzed by a CLIA-approved targeted NGS platform for somatic alterations. 37 had germline testing results available. We performed integrative analysis of both VC and DC. Results: Somatic mutations found in VC were NF2 (24%), SETD2 (13%), SMARCB1 (9%), TP53 (9%), TSC1 (9%), FH (8%), TSC2 (5%), MTOR (5%), EP300 (5%), BAP1 (5%), PBRM1 (5%) and PIK3CA (5%), highly consistent with findings in DC. Germline alterations [FH (11), SDHB (4), and SMARCB1 (1)] were detected in previously unsuspected patients. Integrative analysis supported the presence of NF2-loss (NF2), hyperactive mTOR-driven (MTOR), FH/SDH-deficient (FH/SDH), and chromatin/DNA damage response (Chrom/DDR) molecular subsets. Univariate analysis of combined DC and VC (n = 137, median f/u 26 mos, death 74%) showed a significantly higher risk associated with NF2 subset than the MTOR group (Table). Clonality analysis confirmed NF2 inactivating mutation as a main driver in the NF2 subset. Rare cases with alterations indicating sensitivity or resistance to immunotherapy were also identified. Conclusions: Molecular features of high-grade uRCC improve risk stratification and provide rationale for distinct management strategies.