Von Hippel-Lindau disease: genes and variants
Explore variant evidence for Von Hippel-Lindau disease across 2 analyzed proteins (VHL, EPAS1). Linked ClinVar records include 147 pathogenic or likely pathogenic variants, 293 variants of uncertain significance and 164 with conflicting classifications.
Coverage includes proteins already analyzed in CATVariant, not every gene involved in this condition. Database links are associations, not an assessment of clinical gene–disease validity. Computable evidence prioritizes variants for expert review and does not reclassify them. Source labels are pooled across this disease family.
Data updated 2026-10-10. Automated aggregation, not a clinical review date.
Download variant evidence (CSV)
Genes linked to Von Hippel-Lindau disease
VHL: von Hippel-Lindau disease tumor suppressor
It targets hydroxylated HIF-alpha proteins for ubiquitin-mediated degradation when oxygen is sufficient, keeping hypoxia-response programs suppressed. Loss of function stabilizes HIF signaling and causes von Hippel-Lindau tumor-predisposition syndrome while also driving most clear-cell renal carcinomas.
147 ClinVar pathogenic / likely pathogenic and 456 uncertain variants in VHL have source records linked to Von Hippel-Lindau disease. Association strength is not clinical gene validity.
EPAS1: Endothelial PAS domain-containing protein 1
When stabilized by hypoxia, it activates hypoxia-responsive genes controlling erythropoiesis, angiogenesis, iron metabolism, and cellular adaptation to low oxygen. Activating variants can cause familial erythrocytosis, while somatic dysregulation is central to clear-cell renal carcinoma and some paragangliomas.
0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in EPAS1 have source records linked to Von Hippel-Lindau disease. Association strength is not clinical gene validity.
Weakly linked (only a few uncertain records): BRAF.
Where Von Hippel-Lindau disease variants cluster
- VHL Interaction with Elongin BC complex (positions 157–166): 17 of 147 ClinVar pathogenic / likely pathogenic variants, 2.5× more than its size predicts.
ClinVar pathogenic and likely pathogenic variants linked to Von Hippel-Lindau disease
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| VHL S65W | 65 | Pathogenic / likely pathogenic (★★★) | |
| VHL W88C | 88 | Pathogenic / likely pathogenic (★★★) | |
| VHL R64P | 64 | Pathogenic / likely pathogenic (★★★) | |
| VHL N78S | 78 | Pathogenic / likely pathogenic (★★★) | |
| VHL P86L | 86 | Pathogenic / likely pathogenic (★★★) | |
| VHL R167Q | 167 | Pathogenic / likely pathogenic (★★★) | |
| VHL R82L | 82 | Pathogenic / likely pathogenic (★★) | |
| VHL P86S | 86 | Pathogenic / likely pathogenic (★★) | |
| VHL G93V | 93 | Pathogenic / likely pathogenic (★★) | |
| VHL G93S | 93 | Pathogenic / likely pathogenic (★★) | |
| VHL Y98H | 98 | Pathogenic / likely pathogenic (★★) | |
| VHL L101P | 101 | Involved in binding to CCT complex | Pathogenic / likely pathogenic (★★) |
| VHL R107H | 107 | Involved in binding to CCT complex | Pathogenic / likely pathogenic (★★) |
| VHL S111R | 111 | Involved in binding to CCT complex | Pathogenic / likely pathogenic (★★) |
| VHL Y112C | 112 | Involved in binding to CCT complex | Pathogenic / likely pathogenic (★★) |
| VHL D121G | 121 | Involved in binding to CCT complex | Pathogenic / likely pathogenic (★★) |
| VHL P154S | 154 | Involved in binding to CCT complex | Pathogenic / likely pathogenic (★★) |
| VHL R161Q | 161 | Interaction with Elongin BC complex | Pathogenic / likely pathogenic (★★) |
| VHL R167W | 167 | Pathogenic / likely pathogenic (★★) | |
| VHL Y175C | 175 | Pathogenic / likely pathogenic (★★) | |
| VHL L178P | 178 | Pathogenic / likely pathogenic (★★) | |
| VHL S65L | 65 | Pathogenic / likely pathogenic (★★) | |
| VHL E70K | 70 | Pathogenic / likely pathogenic (★★) | |
| VHL N78T | 78 | Pathogenic / likely pathogenic (★★) | |
| VHL N78D | 78 | Pathogenic / likely pathogenic (★★) | |
| VHL S80I | 80 | Pathogenic / likely pathogenic (★★) | |
| VHL S80N | 80 | Pathogenic / likely pathogenic (★★) | |
| VHL S80G | 80 | Pathogenic / likely pathogenic (★★) | |
| VHL S80R | 80 | Pathogenic / likely pathogenic (★★) | |
| VHL R82P | 82 | Pathogenic / likely pathogenic (★★) | |
| VHL V84M | 84 | Pathogenic / likely pathogenic (★★) | |
| VHL P86R | 86 | Pathogenic / likely pathogenic (★★) | |
| VHL P86A | 86 | Pathogenic / likely pathogenic (★★) | |
| VHL W88R | 88 | Pathogenic / likely pathogenic (★★) | |
| VHL G93R | 93 | Pathogenic / likely pathogenic (★★) | |
| VHL G93D | 93 | Pathogenic / likely pathogenic (★★) | |
| VHL Y98C | 98 | Pathogenic / likely pathogenic (★★) | |
| VHL Y98S | 98 | Pathogenic / likely pathogenic (★★) | |
| VHL L101R | 101 | Involved in binding to CCT complex | Pathogenic / likely pathogenic (★★) |
| VHL R107P | 107 | Involved in binding to CCT complex | Pathogenic / likely pathogenic (★★) |
| VHL S111G | 111 | Involved in binding to CCT complex | Pathogenic / likely pathogenic (★★) |
| VHL Y112N | 112 | Involved in binding to CCT complex | Pathogenic / likely pathogenic (★★) |
| VHL Y112S | 112 | Involved in binding to CCT complex | Pathogenic / likely pathogenic (★★) |
| VHL G114R | 114 | Involved in binding to CCT complex | Pathogenic / likely pathogenic (★★) |
| VHL G114S | 114 | Involved in binding to CCT complex | Pathogenic / likely pathogenic (★★) |
| VHL H115Q | 115 | Involved in binding to CCT complex | Pathogenic / likely pathogenic (★★) |
| VHL H115R | 115 | Involved in binding to CCT complex | Pathogenic / likely pathogenic (★★) |
| VHL L118P | 118 | Involved in binding to CCT complex | Pathogenic / likely pathogenic (★★) |
| VHL L118R | 118 | Involved in binding to CCT complex | Pathogenic / likely pathogenic (★★) |
| VHL R120G | 120 | Involved in binding to CCT complex | Pathogenic / likely pathogenic (★★) |
| VHL L128P | 128 | Involved in binding to CCT complex | Pathogenic / likely pathogenic (★★) |
| VHL N131K | 131 | Involved in binding to CCT complex | Pathogenic / likely pathogenic (★★) |
| VHL N131Y | 131 | Involved in binding to CCT complex | Pathogenic / likely pathogenic (★★) |
| VHL F136V | 136 | Involved in binding to CCT complex | Pathogenic / likely pathogenic (★★) |
| VHL F136S | 136 | Involved in binding to CCT complex | Pathogenic / likely pathogenic (★★) |
| VHL V155M | 155 | Involved in binding to CCT complex | Pathogenic / likely pathogenic (★★) |
| VHL Q164H | 164 | Interaction with Elongin BC complex | Pathogenic / likely pathogenic (★★) |
| VHL V84L | 84 | Pathogenic / likely pathogenic (★★) | |
| VHL R107G | 107 | Involved in binding to CCT complex | Pathogenic / likely pathogenic (★★) |
| VHL S111N | 111 | Involved in binding to CCT complex | Pathogenic / likely pathogenic (★★) |
Showing 60 of 147.
Uncertain variants prioritized for review in Von Hippel-Lindau disease
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| VHL V130I | 130 | Involved in binding to CCT complex | Conflicting reports (★) | +6: 9 other pathogenic changes within 3 positions; V130F at the same position is pathogenic; REVEL 0.824 |
| VHL R64H | 64 | Conflicting reports (★) | +6: 8 other pathogenic changes within 3 positions; R64P at the same position is pathogenic; REVEL 0.798 | |
| VHL I151V | 151 | Involved in binding to CCT complex | Conflicting reports (★) | +6: 10 other pathogenic changes within 3 positions; I151T at the same position is pathogenic; REVEL 0.780 |
| VHL P154R | 154 | Involved in binding to CCT complex | Uncertain (★★★) | +6: 10 other pathogenic changes within 3 positions; P154L at the same position is pathogenic; REVEL 0.942 |
| VHL D197A | 197 | Uncertain (★★) | +6: 5 other pathogenic changes within 3 positions; D197N at the same position is pathogenic; REVEL 0.935 | |
| VHL R82C | 82 | Uncertain (★★) | +6: 10 other pathogenic changes within 3 positions; R82P at the same position is pathogenic; REVEL 0.944 | |
| VHL F76C | 76 | Uncertain (★★) | +6: 8 other pathogenic changes within 3 positions; F76Y at the same position is pathogenic; REVEL 0.917 | |
| VHL F76L | 76 | Uncertain (★★) | +6: 8 other pathogenic changes within 3 positions; F76Y at the same position is pathogenic; REVEL 0.893 | |
| VHL F136L | 136 | Involved in binding to CCT complex | Uncertain (★★) | +6: 3 other pathogenic changes within 3 positions; F136V at the same position is pathogenic; REVEL 0.863 |
| VHL L188V | 188 | Uncertain (★★★) | +6: 4 other pathogenic changes within 3 positions; L188R at the same position is pathogenic; REVEL 0.796 |
Which prediction tools work for Von Hippel-Lindau disease
Observed separation of ClinVar pathogenic / likely pathogenic from benign / likely benign variants (AUROC × 100). This benchmark is not a clinical recommendation.
- CATVariant: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- REVEL: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- AlphaMissense: 96 out of 100
- MetaLR: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- MutPred2: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CADD: 92 out of 100
- PolyPhen-2: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- AlphaGenome (regulatory): 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- SIFT: 80 out of 100
- phyloP: 69 out of 100
- AlphaGenome (splicing): 55 out of 100 (learned from overlapping clinical labels, so this is optimistic)
Diseases related to Von Hippel-Lindau disease
- Renal cell carcinoma, also linked to EPAS1 and VHL
- Chuvash polycythemia, also linked to VHL
- Pheochromocytoma, also linked to VHL
- Erythrocytosis, familial, 6, also linked to EPAS1
- Inherited phaeochromocytoma and paraganglioma excluding NF1, also linked to VHL
- Nonpapillary renal cell carcinoma, also linked to VHL
Frequently asked questions
Which genes have records linked to Von Hippel-Lindau disease?
This view contains 2 analyzed proteins: VHL, EPAS1. Links come from clinical records and association databases. They do not imply that every listed gene is a validated cause, and missing genes may not yet be analyzed.
What do the clinical classifications mean?
Linked records include 147 pathogenic or likely pathogenic variants, 293 variants of uncertain significance and 164 with conflicting classifications. Labels summarize source records; multi-condition records may not make a separate assertion for this disease. Check the original record and review status.
Does the evidence score change a VUS classification?
No. 10 VUS or conflicting variants reach the likely-pathogenic points range on the computable criteria available here. This is a research prioritization signal, not a clinical classification. Patient, family and other required evidence may be missing.
Can I download the variant evidence?
Download the CSV for all 636 variants in the selected disease scope, including clinical labels, review status, evidence criteria, predictor scores, functional measurements and population frequency where available.
About this data
Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from eligible public CATVariant analyses of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.
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