Is VHL p.Pro103Ser (c.307C>T) pathogenic?

VHL p.Pro103Ser (c.307C>T) is classified Uncertain significance in VHL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-11). AlphaMissense: likely pathogenic (0.6873); Absent from gnomAD v4.1; Associated with Chuvash polycythemia.

What condition is associated with VHL p.Pro103Ser (c.307C>T)?

VHL p.Pro103Ser (c.307C>T) is associated with Chuvash polycythemia, von Hippel-Lindau disease (ClinVar).

How common is VHL p.Pro103Ser (c.307C>T) in the general population?

VHL p.Pro103Ser (c.307C>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.Pro103Ser (c.307C>T)?

AlphaMissense predicts likely pathogenic (score 0.6873) — an in-silico prediction, not a clinical call.

VHL p.Pro103Ser

c.307C>T · rs864622267 · VCV2934338

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6873 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Chuvash polycythemia

Computational evidence

Protein change
AlphaMissense	0.6873	likely pathogenic
REVEL	0.659	pathogenic-leaning
SaProt	LLR -9.00	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.5	GERP 1.5, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 8,114 bp · p 0.039 · regional, not allelic
Overall
CADD	23.8	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.Pro103Ser
Coding: c.307C>T
MANE Select: NM_000551
dbSNP: rs864622267
Type: single nucleotide variant
Location: chr3:10142154 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 143 PDB
Residue 103: the 'involved in binding to cct complex' 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

For Chuvash erythrocytosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

VHL p.Pro103= Benign/Likely benign ★★ same residue
VHL p.Pro103Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
VHL p.Pro103Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
VHL p.Pro103fs Pathogenic ★ 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

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-pro103ser (accessed [today's date]).

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