Recently identified molecular tumor markers have numerous potential applications in the diagnosis, therapy and prognostic prediction of renal cell carcinoma (RCC). Through bioinformatics‑based screening approaches together with validation of western blot and immunohistochemical data, the present study identified a novel renal cancer‑associated gene, preliminarily named Renal Cancer Differentiation Gene 1 (RCDG1), originally known as chromosome 4 open reading frame 46 (C4orf46). RCDG1 expression was evaluated by western blot analysis of RCC and adjacent normal tissues, renal cancer cell lines and normal kidney HEK293T cells. Additionally, RCDG1 expression was assessed in 124 RCC paraffin sections, including 92 paired adjacent normal tissues, by immunohistochemistry. The results showed that RCDG1 was significantly downregulated in RCC tissues as compared with normal adjacent tissues (P<0.001), and the expression of RCDG1 in clear cell (cc) RCC tissues was significantly lower as compared with that of non‑ccRCC tissues (P=0.005). Furthermore, statistical analysis revealed RCDG1 expression was negatively correlated with the Fuhrman grade in ccRCC (P=0.008). A reduction in RCDG1 expression may be associated with the oncogenesis of RCC and the differentiation of ccRCC. Further studies may provide more information about the function of RCDG1 gene in RCC.