Is VHL p.Arg58= (c.174G>A) pathogenic?

VHL p.Arg58= (c.174G>A) is classified Likely benign in VHL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-15). Ultra-rare (popmax 0.0168%, mid); Associated with Chuvash polycythemia.

What condition is associated with VHL p.Arg58= (c.174G>A)?

VHL p.Arg58= (c.174G>A) is associated with Chuvash polycythemia, von Hippel-Lindau disease (ClinVar).

How common is VHL p.Arg58= (c.174G>A) in the general population?

VHL p.Arg58= (c.174G>A) is ultra-rare (popmax 0.0168%, mid) (gnomAD).

How is Chuvash erythrocytosis inherited?

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

VHL p.Arg58=

c.174G>A · rs2125124907 · VCV1586479

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, mid)

Conditions

Chuvash polycythemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.82	GERP 1.7, phastCons 0.013
Overall
CADD	10.35	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0168% Middle Eastern · 1/5,966 alleles

Overall 6.28e-05% 1/1,592,978 alleles · ultra-rare exomes 1/1,440,612 · genomes 0/152,366 · 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.Arg58=
Coding: c.174G>A
MANE Select: NM_000551
dbSNP: rs2125124907
Type: single nucleotide variant
Location: chr3:10142021 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 143 PDB
Residue 58: 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.Arg58Gln Uncertain significance ★★ ⚠ same residue
VHL p.Arg58Trp 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
VHL p.Ser65Trp Pathogenic ★★★ same condition
VHL p.Trp88Cys 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-arg58 (accessed [today's date]).

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