VHL
Chr 3ARADvon Hippel-Lindau tumor suppressor
Also known as: HRCA1, RCA1, VHL1, pVHL
The VHL protein functions as a component of an E3 ubiquitin ligase complex that targets hypoxia-inducible factor (HIF) for degradation, regulating oxygen-dependent gene expression and other cellular processes including cilia formation and extracellular matrix formation. Mutations cause von Hippel-Lindau syndrome with cerebellar hemangioblastomas, pheochromocytomas, and renal cell carcinomas, as well as isolated familial erythrocytosis, with both autosomal dominant and recessive inheritance patterns reported. The pathogenic mechanism involves gain-of-function effects leading to dysregulated HIF signaling and abnormal cellular responses to oxygen levels.
Definitive — sufficient evidence for diagnostic panels
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Tolerant to missense variation
This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
300 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 18 | 4 | 14 | 0 | 36 |
Likely Pathogenic | 4 | 6 | 3 | 1 | 14 |
VUS | 14 | 82 | 35 | 1 | 132 |
Likely Benign | 2 | 13 | 23 | 29 | 67 |
Benign | 0 | 4 | 7 | 12 | 23 |
Conflicting | — | 9 | |||
| Total | 38 | 109 | 82 | 43 | 281 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
VHL · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Canadian Profiling and Targeted Agent Utilization Trial (CAPTUR)
RECRUITINGPrevalence Of Germline Gene Mutations In Patients With Myeloproliferative Neoplasms With Family History
NOT YET RECRUITINGNational Eye Institute Biorepository for Retinal Diseases
RECRUITINGFamilial Investigations of Childhood Cancer Predisposition
RECRUITINGMyVHL: Patient Natural History Study
RECRUITINGA Study of HC-7366 in Combination With Belzutifan (WELIREG™) in Patients With Renal Cell Carcinoma
RECRUITINGA Phase 2 Study of Belzutifan (PT2977, MK-6482) for the Treatment of Von Hippel Lindau (VHL) Disease-Associated Renal Cell Carcinoma (RCC) (MK-6482-004)
ACTIVE NOT RECRUITINGGenetic Bases of Neuroendocrine Neoplasms in Mexican Patients
RECRUITINGVon Hippel-Lindau (VHL): Clinical Manifestations, Diagnosis, Management and Molecular Bases of Inherited Renal and Other Urologic Malignant Disorders
RECRUITINGPropranolol and Von Hippel-Lindau Disease
RECRUITINGTAPUR: Testing the Use of Food and Drug Administration (FDA) Approved Drugs That Target a Specific Abnormality in a Tumor Gene in People With Advanced Stage Cancer
RECRUITINGMechanisms of Somatic Mutation and Tumor Initiation in Pre-malignant Kidney Tubule Cells
RECRUITINGExternal Resources
Links to major genomics databases and tools