VHL (von Hippel-Lindau tumor suppressor) is part of an E3 ubiquitin protein ligase complex, which promotes degradation of HIF-alpha. Simple variants in VHL are seen in about 6% of all tumors, including 36% of kidney tumors, where they are diagnostic for clear cell renal cell carcinoma. VHL contributes to von Hippel-Lindau disease and sporadic tumors, including clear cell renal carcinoma. VHL-mutant tumors may be responsive to mTOR and VEGFR inhibitors.