The study validated five GWAS-identified SNPs (rs1049380 and rs10771279 in ITPR2, rs4903064 in DPF3, rs7579899 in EPAS1, rs35252396 in PVT1/MYC) as potential renal cell carcinoma (RCC) biomarkers in a Spanish cohort of 168 patients and 259 healthy controls. controls. Genotypes from buccal swabs and gene expression in 33 paired samples of tumor and normal tissue were analyzed. The C/C genotype of rs10771279 (ITPR2) had a nominally protective effect (OR: 0.41) with higher ITPR2 expression in healthy tissues. C/C genotype rs4903064 (DPF3) was nominally associated with increased risk of RCC (OR: 2.21) and higher DPF3 expression, A/A genotype rs7579899 (EPAS1) with risk (OR: 1.78), while rs35252396 (PVT1/MYC) with no association with risk but with higher expression in RCC tissue. The G allele of rs1049380 (ITPR2) was significantly associated with reduced 5-year survival in patients with and without metastases, the AC genotype of rs35252396 had the nominal highest risk in 5-year survival models. The study confirms the biological relevance of these GWAS loci and suggests ITPR2 rs1049380 as a prognostic marker, with the need for validation in larger cohorts.