Is VHL p.Pro103= (c.309T>C) pathogenic?

VHL p.Pro103= (c.309T>C) is classified Benign/Likely benign in VHL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-11). Very rare (popmax 8.48e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with VHL p.Pro103= (c.309T>C)?

VHL p.Pro103= (c.309T>C) is associated with hereditary neoplastic syndrome, von Hippel-Lindau disease, Chuvash polycythemia (ClinVar).

How common is VHL p.Pro103= (c.309T>C) in the general population?

VHL p.Pro103= (c.309T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

VHL p.Pro103=

c.309T>C · rs1262511541 · VCV1077591

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

hereditary neoplastic syndrome

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 -3.4	GERP -2.6
Overall
CADD	7.055	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,452 alleles

Overall 6.26e-05% 1/1,598,712 alleles · very rare exomes 1/1,446,498 · genomes 0/152,214 · 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.Pro103=
Coding: c.309T>C
MANE Select: NM_000551
dbSNP: rs1262511541
Type: single nucleotide variant
Location: chr3:10142156 (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

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.Pro103Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
VHL p.Pro103Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
VHL p.Pro103Ser Uncertain significance ★ ⚠ 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-pro103 (accessed [today's date]).

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