Is VHL p.Phe76fs (c.222_225dup) pathogenic?

VHL p.Phe76fs (c.222225dup) is classified Likely pathogenic in VHL (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-04-06). No gnomAD frequency available for this variant; Associated with von Hippel-Lindau disease.

What condition is associated with VHL p.Phe76fs (c.222_225dup)?

VHL p.Phe76fs (c.222_225dup) is associated with von Hippel-Lindau disease (ClinVar).

How common is VHL p.Phe76fs (c.222_225dup) in the general population?

VHL p.Phe76fs (c.222_225dup) is no gnomAD frequency available for this variant (gnomAD).

How is Von Hippel-Lindau disease inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

VHL p.Phe76fs

c.222_225dup · rs2470158146 · VCV1723891

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

von Hippel-Lindau disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 1 of 3
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.6	GERP 0.56, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: VHL
Protein: p.Phe76fs
Coding: c.222_225dup
MANE Select: NM_000551
dbSNP: rs2470158146
Type: Duplication
Location: chr3:10142068 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 143 PDB
Residue 76: a β-strand; a UniProt-annotated variant site (in vhld; type i)

Full VHL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

von Hippel-Lindau disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Von Hippel-Lindau disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 100 000 (United Kingdom)

Similar variants

VHL p.Phe76del Pathogenic/Likely pathogenic ★★ same residue
VHL p.Phe76Tyr Pathogenic/Likely pathogenic ★★ same residue
VHL p.Phe76Cys Uncertain significance ★★ ⚠ same residue
VHL p.Phe76Leu Uncertain significance ★★ ⚠ same residue
VHL p.Phe76= Benign/Likely benign ★★ same residue
VHL p.Phe76Val Likely pathogenic ★ same residue
VHL p.Phe76Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
VHL p.Arg60fs Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/vhl-p-phe76fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown