Is VHL p.Pro40= (c.120G>C) pathogenic?

VHL p.Pro40= (c.120G>C) is classified Benign in VHL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-10). Absent from gnomAD v4.1; Associated with von Hippel-Lindau disease.

What condition is associated with VHL p.Pro40= (c.120G>C)?

VHL p.Pro40= (c.120G>C) is associated with von Hippel-Lindau disease (ClinVar).

How common is VHL p.Pro40= (c.120G>C) in the general population?

VHL p.Pro40= (c.120G>C) 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.

VHL p.Pro40=

c.120G>C · VCV4071060

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 -0.084	GERP -2.9
Overall
CADD	7.858	PHRED · no single calibrated threshold — expert panels disagree

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.Pro40=
Coding: c.120G>C
MANE Select: NM_000551
Type: single nucleotide variant
Location: chr3:10141967 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 143 PDB
Residue 40: the '8 x 5 aa tandem repeats of g-[pavg]-e-e-[daysle]' region; the 'disordered' region

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

For Von Hippel-Lindau disease (Orphanet):

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

Similar variants

VHL p.Pro40Leu Benign ★★★ same residue
VHL p.Pro40Ala Uncertain significance ★★ ⚠ same residue
VHL p.Pro40Arg Uncertain significance ★★ ⚠ same residue
VHL p.Pro40Ser Uncertain significance ★★ ⚠ same residue
VHL p.Pro40Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
VHL p.Pro40Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
VHL p.Arg64Pro Pathogenic ★★★ same condition
VHL p.Asn78Ser 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-pro40 (accessed [today's date]).

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