Is VHL p.Pro86Arg (c.257C>G) pathogenic?

VHL p.Pro86Arg (c.257C>G) is classified Pathogenic/Likely pathogenic in VHL (ClinVar, Multiple submitters, 7 submitters; last evaluated 2024-07-11). AlphaMissense: likely pathogenic (0.9948); Absent from gnomAD v4.1; Associated with von Hippel-Lindau disease.

What condition is associated with VHL p.Pro86Arg (c.257C>G)?

VHL p.Pro86Arg (c.257C>G) is associated with von Hippel-Lindau disease, Chuvash polycythemia, hereditary neoplastic syndrome (ClinVar).

How common is VHL p.Pro86Arg (c.257C>G) in the general population?

VHL p.Pro86Arg (c.257C>G) is absent from gnomAD v4.1 (gnomAD).

How is Von Hippel-Lindau disease inherited?

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

What do computational predictors say about VHL p.Pro86Arg (c.257C>G)?

AlphaMissense predicts likely pathogenic (score 0.9948) — an in-silico prediction, not a clinical call.

VHL p.Pro86Arg

c.257C>G · rs730882034 · VCV223170

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9948 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

von Hippel-Lindau disease

Computational evidence

Protein change
AlphaMissense	0.9948	likely pathogenic ✓ concordant with ClinVar · top 4% in VHL
REVEL	0.88	moderately pathogenic-leaning
SaProt	LLR -16.25	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 1.7, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 8,114 bp · p 0.039 · regional, not allelic
Overall
CADD	23.4	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.

Cancer therapy — CIViC

Disease	Level	Significance
Von Hippel-Lindau Disease	C	Predisposition
Von Hippel-Lindau Disease	C	Predisposition
Von Hippel-Lindau Disease	C	Uncertain Significance
Von Hippel-Lindau Disease	C	Uncertain Significance
Von Hippel-Lindau Disease	C	Uncertain Significance
Von Hippel-Lindau Disease	C	Uncertain Significance
Von Hippel-Lindau Disease	C
Von Hippel-Lindau Disease	C

Variant & gene context

Gene: VHL
Protein: p.Pro86Arg
Coding: c.257C>G
MANE Select: NM_000551
dbSNP: rs730882034
Type: single nucleotide variant
Location: chr3:10142104 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 143 PDB
Residue 86: a β-strand; a UniProt-annotated variant site (in vhld; type i); a UniProt-annotated variant site (in vhld)

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

Disease context

von Hippel-Lindau disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Chuvash polycythemia hereditary neoplastic syndrome

For Von Hippel-Lindau disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 100 000 (United Kingdom)

Similar variants

VHL p.Pro86Leu Pathogenic ★★★ same residue
VHL p.Pro86Ala Pathogenic/Likely pathogenic ★★ same residue
VHL p.Pro86Ser Pathogenic/Likely pathogenic ★★ same residue
VHL p.Pro86= 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.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-pro86arg (accessed [today's date]).

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