Is VHL p.Pro59Ser (c.175C>T) pathogenic?

VHL p.Pro59Ser (c.175C>T) is classified Conflicting classifications of pathogenicity in VHL (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-05-18). AlphaMissense: likely benign (0.0857); No allele count reported in gnomAD v4.1 (AN 1,593,494); Associated with von Hippel-Lindau disease.

What condition is associated with VHL p.Pro59Ser (c.175C>T)?

VHL p.Pro59Ser (c.175C>T) is associated with von Hippel-Lindau disease, Chuvash polycythemia, hereditary neoplastic syndrome (ClinVar).

How common is VHL p.Pro59Ser (c.175C>T) in the general population?

VHL p.Pro59Ser (c.175C>T) is no allele count reported in gnomAD v4.1 (AN 1,593,494) (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.Pro59Ser (c.175C>T)?

AlphaMissense predicts likely benign (score 0.0857) — an in-silico prediction, not a clinical call.

VHL p.Pro59Ser

c.175C>T · rs876659041 · VCV231233

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0857 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,593,494)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

von Hippel-Lindau disease

Computational evidence

Protein change
AlphaMissense	0.0857	likely benign
REVEL	0.484	indeterminate
SaProt	LLR -9.90	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.12	GERP 1.7
Regional constraint	o/e 1.12	unconstrained · MANE · 8,114 bp · p 0.039 · regional, not allelic
Overall
CADD	14.27	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

No allele count reported in gnomAD v4.1 (AN 1,593,494). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: VHL
Protein: p.Pro59Ser
Coding: c.175C>T
MANE Select: NM_000551
dbSNP: rs876659041
Type: single nucleotide variant
Location: chr3:10142022 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 143 PDB
Residue 59: an α-helix; 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

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.Pro59Gln Uncertain significance ★★ ⚠ same residue
VHL p.Pro59= Benign/Likely benign ★★ same residue
VHL p.Pro59Leu 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
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-pro59ser (accessed [today's date]).

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