Is VHL p.Pro99Ala (c.295C>G) pathogenic?

VHL p.Pro99Ala (c.295C>G) is classified Uncertain significance in VHL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-09). AlphaMissense: likely benign (0.1669); Very rare (popmax 0.00669%, eas); Associated with Chuvash polycythemia.

What condition is associated with VHL p.Pro99Ala (c.295C>G)?

VHL p.Pro99Ala (c.295C>G) is associated with Chuvash polycythemia, von Hippel-Lindau disease (ClinVar).

How common is VHL p.Pro99Ala (c.295C>G) in the general population?

VHL p.Pro99Ala (c.295C>G) is very rare (popmax 0.00669%, eas) (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.Pro99Ala (c.295C>G)?

AlphaMissense predicts likely benign (score 0.1669) — an in-silico prediction, not a clinical call.

VHL p.Pro99Ala

c.295C>G · rs549807529 · VCV1037470

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1669 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Chuvash polycythemia

Computational evidence

Protein change
AlphaMissense	0.1669	likely benign
REVEL	0.518	indeterminate
SaProt	LLR -6.05	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 1.5, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 8,114 bp · p 0.039 · regional, not allelic
Overall
CADD	19.58	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 0.00669% East Asian · 3/44,856 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000892%

Overall 0.000375% 6/1,599,914 alleles · very rare exomes 6/1,447,636 · genomes 0/152,278 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,952
South Asian	0.0011%	91,022
European (non-Finnish)	0.00017%	589,803

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.Pro99Ala
Coding: c.295C>G
MANE Select: NM_000551
dbSNP: rs549807529
Type: single nucleotide variant
Location: chr3:10142142 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 143 PDB
Residue 99: an α-helix

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.Pro99= Benign/Likely benign ★★ same residue
VHL p.Pro99Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
VHL p.Pro99Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
VHL p.Pro99Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
VHL p.Arg64Pro Pathogenic ★★★ same condition
VHL p.Asn78Ser Pathogenic ★★★ ⚠ same condition
VHL p.Glu70Ter Pathogenic ★★★ same condition
VHL p.Pro86Leu 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-pro99ala (accessed [today's date]).

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