Is VHL p.Pro2Ala (c.4C>G) pathogenic?

VHL p.Pro2Ala (c.4C>G) is classified Uncertain significance in VHL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.0968); Very rare (popmax 0.00138%, afr); Associated with Chuvash polycythemia.

What condition is associated with VHL p.Pro2Ala (c.4C>G)?

VHL p.Pro2Ala (c.4C>G) is associated with Chuvash polycythemia, von Hippel-Lindau disease, hereditary neoplastic syndrome (ClinVar).

How common is VHL p.Pro2Ala (c.4C>G) in the general population?

VHL p.Pro2Ala (c.4C>G) is very rare (popmax 0.00138%, afr) (gnomAD).

How is Chuvash erythrocytosis inherited?

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

What do computational predictors say about VHL p.Pro2Ala (c.4C>G)?

AlphaMissense predicts likely benign (score 0.0968) — an in-silico prediction, not a clinical call.

VHL p.Pro2Ala

c.4C>G · rs1034974221 · VCV825356

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0968 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00138%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Chuvash polycythemia

Computational evidence

Protein change
AlphaMissense	0.0968	likely benign
REVEL	0.125	moderately benign-leaning
SaProt	LLR -5.12	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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
Overall
CADD	14.12	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00138% African / African-American · 1/72,334 alleles

Overall 0.00013% 2/1,535,324 alleles · very rare exomes 1/1,383,092 · genomes 1/152,232 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00138%	72,334
European (non-Finnish)	8.77e-05%	1,139,773

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.Pro2Ala
Coding: c.4C>G
MANE Select: NM_000551
dbSNP: rs1034974221
Type: single nucleotide variant
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 hereditary neoplastic syndrome

For Chuvash erythrocytosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

VHL p.Pro2Arg Uncertain significance ★★ ⚠ same residue
VHL p.Pro2His Uncertain significance ★★ ⚠ same residue
VHL p.Pro2Ser Uncertain significance ★★ ⚠ same residue
VHL p.Pro2Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
VHL p.Pro2Thr Uncertain significance ★ ⚠ same residue
VHL p.Pro2= Likely benign ★ same residue
VHL p.Pro2Phe Uncertain significance ★★ same residue
VHL p.Pro2fs Uncertain significance ★ same residue

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-pro2ala (accessed [today's date]).

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