Is VHL p.Pro97Arg (c.290C>G) pathogenic?

VHL p.Pro97Arg (c.290C>G) is classified Likely benign in VHL (ClinVar, Single submitter, 1 submitter; last evaluated 2026-05-15). AlphaMissense: likely benign (0.2313); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with VHL p.Pro97Arg (c.290C>G)?

VHL p.Pro97Arg (c.290C>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is VHL p.Pro97Arg (c.290C>G) in the general population?

VHL p.Pro97Arg (c.290C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about VHL p.Pro97Arg (c.290C>G)?

AlphaMissense predicts likely benign (score 0.2313) — an in-silico prediction, not a clinical call.

VHL p.Pro97Arg

c.290C>G · rs2125125249 · VCV3232219

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2313 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2313	likely benign
REVEL	0.65	pathogenic-leaning
SaProt	LLR -7.83	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.6	GERP 1.5, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 8,114 bp · p 0.039 · regional, not allelic
Overall
CADD	20.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: VHL
Protein: p.Pro97Arg
Coding: c.290C>G
MANE Select: NM_000551
dbSNP: rs2125125249
Type: single nucleotide variant
Location: chr3:10142137 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 143 PDB
Residue 97: a β-strand; a UniProt-annotated variant site (in vhld; type i)

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

Similar variants

VHL p.Pro97Leu Uncertain significance ★★ ⚠ same residue
VHL p.Pro97= Benign/Likely benign ★★ same residue
VHL p.Pro97Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
VHL p.Pro97Thr 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-pro97arg (accessed [today's date]).

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