Is VHL p.Glu55fs (c.163dup) pathogenic?

VHL p.Glu55fs (c.163dup) is classified Pathogenic in VHL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-05). Very rare (popmax 8.56e-05%, nfe); Associated with von Hippel-Lindau disease.

What condition is associated with VHL p.Glu55fs (c.163dup)?

VHL p.Glu55fs (c.163dup) is associated with von Hippel-Lindau disease, Chuvash polycythemia, hereditary neoplastic syndrome (ClinVar).

How common is VHL p.Glu55fs (c.163dup) in the general population?

VHL p.Glu55fs (c.163dup) is very rare (popmax 8.56e-05%, nfe) (gnomAD).

How is Von Hippel-Lindau disease inherited?

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

VHL p.Glu55fs

c.163dup · rs869025615 · VCV223159

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.56e-05%, nfe)

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 3.7	GERP 0.52, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.56e-05% European (non-Finnish) · 1/1,168,624 alleles

Overall 6.3e-05% 1/1,587,584 alleles · very rare exomes 1/1,435,340 · genomes 0/152,244 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: VHL
Protein: p.Glu55fs
Coding: c.163dup
MANE Select: NM_000551
dbSNP: rs869025615
Type: Duplication
Location: chr3:10142008 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 143 PDB
Residue 55: the 'disordered' region

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

Also linked: Chuvash polycythemia hereditary neoplastic syndrome

For Von Hippel-Lindau disease (Orphanet):

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

Similar variants

VHL p.Glu55Val Uncertain significance ★★ ⚠ same residue
VHL p.Glu55= Benign/Likely benign ★★ same residue
VHL p.Glu55Asp Uncertain significance ★ ⚠ same residue
VHL p.Glu55Gln Uncertain significance ★ ⚠ same residue
VHL p.Glu55Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
VHL p.Arg60fs Pathogenic ★★ same condition
VHL p.Arg64fs Pathogenic/Likely pathogenic ★★ same condition
VHL p.Arg69fs 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-glu55fs (accessed [today's date]).

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