Is VHL p.Pro40Ser (c.118C>T) pathogenic?

VHL p.Pro40Ser (c.118C>T) is classified Uncertain significance in VHL (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-07). AlphaMissense: likely benign (0.0794); Very rare (popmax 0.000261%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with VHL p.Pro40Ser (c.118C>T)?

VHL p.Pro40Ser (c.118C>T) is associated with hereditary neoplastic syndrome, von Hippel-Lindau disease, Chuvash polycythemia (ClinVar).

How common is VHL p.Pro40Ser (c.118C>T) in the general population?

VHL p.Pro40Ser (c.118C>T) is very rare (popmax 0.000261%, nfe) (gnomAD).

What do computational predictors say about VHL p.Pro40Ser (c.118C>T)?

AlphaMissense predicts likely benign (score 0.0794) — an in-silico prediction, not a clinical call.

VHL p.Pro40Ser

c.118C>T · rs776399733 · VCV1373310

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0794 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000261%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0794	likely benign
REVEL	0.181	moderately benign-leaning
SaProt	LLR -7.51	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 -0.1	GERP -3
Regional constraint	o/e 1.12	unconstrained · MANE · 8,114 bp · p 0.039 · regional, not allelic
Overall
CADD	15.6	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 0.000261% European (non-Finnish) · 3/1,149,812 alleles

Filtering AF 7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000193% 3/1,553,810 alleles · very rare exomes 2/1,401,636 · genomes 1/152,174 · 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.Pro40Ser
Coding: c.118C>T
MANE Select: NM_000551
dbSNP: rs776399733
Type: single nucleotide variant
Location: chr3:10141965 (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

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.Pro40Leu Benign ★★★ same residue
VHL p.Pro40Ala Uncertain significance ★★ ⚠ same residue
VHL p.Pro40Arg Uncertain significance ★★ ⚠ same residue
VHL p.Pro40Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
VHL p.Pro40Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
VHL p.Pro40= Benign ★ 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-pro40ser (accessed [today's date]).

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