Is VHL p.Pro25Arg (c.74C>G) pathogenic?

VHL p.Pro25Arg (c.74C>G) is classified Uncertain significance in VHL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-29). AlphaMissense: likely benign (0.0822); Very rare (popmax 0.00121%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with VHL p.Pro25Arg (c.74C>G)?

VHL p.Pro25Arg (c.74C>G) is associated with hereditary neoplastic syndrome, von Hippel-Lindau disease, Chuvash polycythemia (ClinVar).

How common is VHL p.Pro25Arg (c.74C>G) in the general population?

VHL p.Pro25Arg (c.74C>G) is very rare (popmax 0.00121%, sas) (gnomAD).

What do computational predictors say about VHL p.Pro25Arg (c.74C>G)?

AlphaMissense predicts likely benign (score 0.0822) — an in-silico prediction, not a clinical call.

VHL p.Pro25Arg

c.74C>G · VCV4558075

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0822 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00121%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0822	likely benign
REVEL	0.275	benign-leaning
SaProt	LLR -7.57	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 1.8	GERP 0.96, phastCons 0.004
Regional constraint	o/e 1.12	unconstrained · MANE · 8,114 bp · p 0.039 · regional, not allelic
Overall
CADD	19.13	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 0.00121% South Asian · 1/82,712 alleles

Overall 6.5e-05% 1/1,539,538 alleles · very rare exomes 1/1,387,200 · genomes 0/152,338 · 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.Pro25Arg
Coding: c.74C>G
MANE Select: NM_000551
Type: single nucleotide variant
Location: chr3:10141921 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 143 PDB
Residue 25: the '8 x 5 aa tandem repeats of g-[pavg]-e-e-[daysle]' region; a UniProt-annotated variant site (in pcc; benign); the 'disordered' region

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: von Hippel-Lindau disease Chuvash polycythemia

Similar variants

VHL p.Pro25Leu Benign ★★★ same residue
VHL p.Pro25Ala Uncertain significance ★★ ⚠ same residue
VHL p.Pro25= Benign/Likely benign ★★ 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

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-pro25arg (accessed [today's date]).

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