Is VHL p.Pro86= (c.258C>G) pathogenic?

VHL p.Pro86= (c.258C>G) is classified Benign/Likely benign in VHL (ClinVar, Multiple submitters, 11 submitters; last evaluated 2025-12-24). Very rare (popmax 0.00935%, afr); Associated with von Hippel-Lindau disease.

What condition is associated with VHL p.Pro86= (c.258C>G)?

VHL p.Pro86= (c.258C>G) is associated with von Hippel-Lindau disease, Chuvash polycythemia, hereditary neoplastic syndrome (ClinVar).

How common is VHL p.Pro86= (c.258C>G) in the general population?

VHL p.Pro86= (c.258C>G) is very rare (popmax 0.00935%, afr) (gnomAD).

How is Von Hippel-Lindau disease inherited?

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

VHL p.Pro86=

c.258C>G · rs781063331 · VCV238104

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00935%, afr)

Conditions

von Hippel-Lindau disease

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 -8.1	GERP -3
Overall
CADD	1.015	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00935% African / African-American · 7/74,906 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.00274% 44/1,603,190 alleles · very rare exomes 42/1,451,026 · genomes 2/152,164 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00935%	10,701
Remaining individualsnot grpmax-eligible	0.00481%	20,784
East Asian	0.00446%	22,429
European (non-Finnish)	0.00263%	38,056
Admixed American	0.00167%	59,958

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.Pro86=
Coding: c.258C>G
MANE Select: NM_000551
dbSNP: rs781063331
Type: single nucleotide variant
Location: chr3:10142105 (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.Pro86Arg Pathogenic/Likely pathogenic ★★ same residue
VHL p.Pro86Ser Pathogenic/Likely pathogenic ★★ 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-pro86 (accessed [today's date]).

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