Is VHL p.Pro61Ser (c.181C>T) pathogenic?

VHL p.Pro61Ser (c.181C>T) is classified Uncertain significance in VHL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-04-29). AlphaMissense: ambiguous (0.3408); Absent from gnomAD v4.1; Associated with Chuvash polycythemia.

What condition is associated with VHL p.Pro61Ser (c.181C>T)?

VHL p.Pro61Ser (c.181C>T) is associated with Chuvash polycythemia, von Hippel-Lindau disease, hereditary neoplastic syndrome (ClinVar).

How common is VHL p.Pro61Ser (c.181C>T) in the general population?

VHL p.Pro61Ser (c.181C>T) is absent from gnomAD v4.1 (gnomAD).

How is Chuvash erythrocytosis inherited?

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

What do computational predictors say about VHL p.Pro61Ser (c.181C>T)?

AlphaMissense predicts ambiguous (score 0.3408) — an in-silico prediction, not a clinical call.

VHL p.Pro61Ser

c.181C>T · rs113612866 · VCV411990

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3408 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Chuvash polycythemia

Computational evidence

Protein change
AlphaMissense	0.3408	ambiguous
REVEL	0.312	indeterminate
SaProt	LLR -6.70	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP -0.49, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 8,114 bp · p 0.039 · regional, not allelic
Overall
CADD	20.8	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.

Variant & gene context

Gene: VHL
Protein: p.Pro61Ser
Coding: c.181C>T
MANE Select: NM_000551
dbSNP: rs113612866
Type: single nucleotide variant
Location: chr3:10142028 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 143 PDB
Residue 61: an α-helix; the 'disordered' region

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

Disease context

Chuvash polycythemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: von Hippel-Lindau disease hereditary neoplastic syndrome

For Chuvash erythrocytosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

VHL p.Pro61= Benign ★★★ same residue
VHL p.Pro61Leu Uncertain significance ★★ ⚠ same residue
VHL p.Pro61Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
VHL p.Pro61Arg Uncertain significance ★ ⚠ same residue
VHL p.Pro61_Val62insArgPro Uncertain significance ★★ same residue
VHL p.Pro61fs Pathogenic ★ 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-pro61ser (accessed [today's date]).

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