Clear cell renal cell carcinoma (ccRCC) exhibits considerable heterogeneity, with approximately 25% of localized cases susceptible to relapse, highlighting the challenge of the absence of reliable predictive biomarkers for personalized treatment. Meanwhile, metastatic renal cell carcinoma is characterized by unfavorable survival rates, and although Sunitinib offers partial benefits, the clinical advantages are often constrained by drug resistance and adverse side effects. Here, MAGI3 was associate with ccRCC progression, as identified through comprehensive bioinformatics analysis of clinical datasets. A low level of MAGI3 emerged as a high-risk factor for ccRCC, indicating its potential as a prognostic marker. Individuals with MAGI3 expression in middle-to-low levels displayed a significantly poorer survival rate, indicating a need for additional treatment even in the early stages of ccRCC. Furthermore, patients with MAGI3 expression in middle-to-high levels exhibited increased sensitivity to Sunitinib compared to those with lower MAGI3 levels, suggesting that individuals with MAGI3 expression at middle levels may potentially benefit from Sunitinib treatment even in the early stages of ccRCC. Through its interaction with the MAS receptor, MAGI3 has been identified as a regulator of cell proliferation and a determinant of Sunitinib resistance in ccRCC, operating via the Ang-(1-7)/MAS/ERK axis. The loss of MAGI3 expression in ccRCC patients activated the ERK signaling pathway, contributing to both cancer progression and Sunitinib resistance. Therefore, our study not only highlight MAGI3's pivotal role in ccRCC progression and Sunitinib resistance, but also reinforces MAGI3's prospective value as a predictive marker.