In summary, the present study comprehensively analyzed FXYD2 expression in ccRCC utilizing several public datasets and our clinical tissue samples and demonstrated that downregulated FXYD2 expression correlated with carcinogenesis, poor prognosis, and increased Treg infiltration in ccRCC, which may function by participating in TGF-β-SMAD2/3, Notch, and PI3K-Akt-mTOR signaling pathways. This evidence concerns the gene SMAD2 and nonpapillary renal cell carcinoma.