Is VHL p.Ala5= (c.15G>A) pathogenic?

VHL p.Ala5= (c.15G>A) is classified Likely benign in VHL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2020-02-06). Very rare (popmax 0.00138%, afr); Associated with Chuvash polycythemia.

What condition is associated with VHL p.Ala5= (c.15G>A)?

VHL p.Ala5= (c.15G>A) is associated with Chuvash polycythemia, von Hippel-Lindau disease, hereditary neoplastic syndrome (ClinVar).

How common is VHL p.Ala5= (c.15G>A) in the general population?

VHL p.Ala5= (c.15G>A) 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.

VHL p.Ala5=

c.15G>A · rs1355874307 · VCV1138466

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00138%, afr)

Conditions

Chuvash polycythemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.93	GERP -2.6, phastCons 0.004
Overall
CADD	8.437	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00138% African / African-American · 1/72,468 alleles

Overall 6.52e-05% 1/1,534,558 alleles · very rare exomes 1/1,382,196 · genomes 0/152,362 · 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.Ala5=
Coding: c.15G>A
MANE Select: NM_000551
dbSNP: rs1355874307
Type: single nucleotide variant
Location: chr3:10141862 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 143 PDB
Residue 5: 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.Ala5Pro Uncertain significance ★★ ⚠ same residue
VHL p.Ala5Ser Uncertain significance ★★ ⚠ same residue
VHL p.Ala5Thr Uncertain significance ★★ ⚠ same residue
VHL p.Ala5Val Uncertain significance ★★ ⚠ same residue
VHL p.Ala5Glu Uncertain significance ★ ⚠ same residue
VHL p.Ala5Gly Uncertain significance ★ ⚠ same residue
VHL p.Ala5fs Conflicting classifications of pathogenicity ★ ⚠ same residue
VHL p.Arg64Pro 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-ala5 (accessed [today's date]).

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