SEMA6A is a multifunctional transmembrane semaphorin protein that participates in various cellular processes, including axon guidance, cell migration, and cancer progression. However, the role of SEMA6A in clear cell renal cell carcinoma (ccRCC) is unclear. Based on high-throughput sequencing data, here we report that SEMA6A is a novel target gene of the VHL-HIF-2 alpha axis and overexpressed in ccRCC. Chromatin immunoprecipitation and reporter assays revealed that HIF-2 alpha directly activated SEMA6A transcription in hypoxic ccRCC cells. Wnt/beta-catenin pathway activation is correlated with the expression of SEMA6A in ccRCC; the latter physically interacted with SEC62 and promoted ccRCC progression through SEC62-dependent beta-catenin stabilization and activation. Depletion of SEMA6A impaired HIF-2 alpha-induced Wnt/beta-catenin pathway activation and led to defective ccRCC cell proliferation both in vitro and in vivo. SEMA6A overexpression promoted the malignant phenotypes of ccRCC, which was reversed by SEC62 depletion. Collectively, this study revealed a potential role for VHL-HIF-2 alpha-SEMA6A-SEC62 axis in the activation of Wnt/beta-catenin pathway. Thus, SEMA6A may act as a potential therapeutic target, especially in VHL-deficient ccRCC.