VHL

Chr 3ARAD

von Hippel-Lindau tumor suppressor

NCBI Gene: 7428 ENSG00000134086 UniProt: P40337

Involved in the ubiquitination and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitination complex (PubMed:10944113, PubMed:17981124, PubMed:19584355). Seems to act as a target recruitment subunit in the E3 ubiquitin ligase complex and recruits hydroxylated hypoxia-inducible factor (HIF) under normoxic conditions (PubMed:10944113, PubMed:17981124). Involved in transcriptional repression through interaction with HIF1A, HIF1AN and histone deacetylases (PubMed:10944113, PubMed:17981124). Ubiquitinates, in an oxygen-responsive manner, ADRB2 (PubMed:19584355). Acts as a negative regulator of mTORC1 by promoting ubiquitination and degradation of RPTOR (PubMed:34290272)

Primary Disease Associations & Inheritance

Erythrocytosis, familial, 2MIM #263400

Hemangioblastoma, cerebellar, somatic

PheochromocytomaMIM #171300

Renal cell carcinoma, somaticMIM #144700

von Hippel-Lindau syndromeMIM #193300

581

ClinVar variants

Pathogenic / LP

0.08

pLI score

Active trials

Clinical Summary— VHL

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Gene-Disease Validity (ClinGen)

von Hippel-Lindau disease · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.08) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

99 Pathogenic / Likely Pathogenic· 300 VUS of 581 total submissions

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.93LOEUF

pLI 0.080

Z-score 1.72

OE 0.36 (0.16–0.93)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

-0.39Z-score

OE missense 1.10 (0.96–1.27)

136 obs / 123.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.36 (0.16–0.93)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.10 (0.96–1.27)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.11

0≤1.21.6

LoF obs/exp: 3 / 8.4Missense obs/exp: 136 / 123.6Syn Z: -0.63

ClinVar Variant Classifications

581 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic74

Likely Pathogenic25

VUS300

Likely Benign139

Benign23

Conflicting20

Pathogenic

Likely Pathogenic

300

VUS

139

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	37	13	24	0	74
Likely Pathogenic	4	15	5	1	25
VUS	22	192	73	13	300
Likely Benign	3	22	48	66	139
Benign	0	3	8	12	23
Conflicting	—				20
Total	66	245	158	92	581

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.

Gene2Phenotype Curations

VHL-related pheochromocytoma

definitive

ADGain Of FunctionAltered Gene Product Structure

Skin

G2P ↗

VHL-related von Hippel-Lindau syndrome

definitive

ADLoss Of FunctionAbsent Gene Product

EyeSkinCancer

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

VON HIPPEL-LINDAU TUMOR SUPPRESSOR; VHL

MIM #608537 · *

Erythrocytosis, familial, 2

MIM #263400