Using publicly available human sequencing datasets (The Cancer Genome Atlas [TCGA] and Gene Expression Omnibus [GEO] Series [GSE73121]) and immunohistochemistry (IHC) analysis, we confirmed that IL6, CASP3, ACTB, ACTG1 and RAP1B, which are referred to as subpopulation‐difference or sub‐diff markers, are co‐regulators of the differentially expressed gene (DEG) network between two metastatic subpopulations and play key roles in RCC metastasis. The gene discussed is CASP3; the disease is renal cell carcinoma.