Notably, two VHL missense mutations in the p53 binding domain, Leu158Val and Arg161Gln, altered p53 signaling but retained HIF1/2α degradation function, thus confirming our hypothesis of differing effects of missense mutations on pVHL functions (summarized in figure 10) Our results may scrutinize the rationale of the systematic use of anti-angiogenic drugs, particularly for those metastatic ccRCC with VHL missense mutations that specifically affect non HIF1/2α binding sites. This evidence concerns the gene HIF1A and nonpapillary renal cell carcinoma.