Is VHL p.Pro2Phe (c.4_5delinsTT) pathogenic?

VHL p.Pro2Phe (c.45delinsTT) is classified Uncertain significance in VHL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-25). Associated with Chuvash polycythemia.

What condition is associated with VHL p.Pro2Phe (c.4_5delinsTT)?

VHL p.Pro2Phe (c.4_5delinsTT) is associated with Chuvash polycythemia, von Hippel-Lindau disease (ClinVar).

How is Chuvash erythrocytosis inherited?

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

VHL p.Pro2Phe

c.4_5delinsTT · VCV3365139

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

Conditions

Chuvash polycythemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.42	GERP -1.8, phastCons 0.005
Regional constraint	o/e 1.12	unconstrained · MANE · 8,114 bp · p 0.039 · regional, not allelic

Variant & gene context

Gene: VHL
Protein: p.Pro2Phe
Coding: c.4_5delinsTT
MANE Select: NM_000551
Type: Indel
Location: chr3:10141851 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 143 PDB
Residue 2: the 'disordered' region

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

Disease context

Chuvash polycythemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: von Hippel-Lindau disease

For Chuvash erythrocytosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

VHL p.Pro2Ala Uncertain significance ★★ ⚠ same residue
VHL p.Pro2Arg Uncertain significance ★★ ⚠ same residue
VHL p.Pro2His Uncertain significance ★★ ⚠ same residue
VHL p.Pro2Ser Uncertain significance ★★ ⚠ same residue
VHL p.Pro2fs Uncertain significance ★ same residue
VHL p.Pro2Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
VHL p.Pro2Thr Uncertain significance ★ ⚠ same residue
VHL p.Gly93Val Pathogenic/Likely 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-pro2phe (accessed [today's date]).

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