Is VHL p.Pro102Ser (c.304C>T) pathogenic?

VHL p.Pro102Ser (c.304C>T) is classified Conflicting classifications of pathogenicity in VHL (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-31). AlphaMissense: likely benign (0.1326); Very rare (popmax 0.00267%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with VHL p.Pro102Ser (c.304C>T)?

VHL p.Pro102Ser (c.304C>T) is associated with hereditary neoplastic syndrome, von Hippel-Lindau disease, Chuvash polycythemia (ClinVar).

How common is VHL p.Pro102Ser (c.304C>T) in the general population?

VHL p.Pro102Ser (c.304C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about VHL p.Pro102Ser (c.304C>T)?

AlphaMissense predicts likely benign (score 0.1326) — an in-silico prediction, not a clinical call.

VHL p.Pro102Ser

c.304C>T · rs532018719 · VCV857493

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1326 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1326	likely benign
REVEL	0.427	indeterminate
SaProt	LLR -7.47	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 2.4	GERP -0.57, phastCons 0.99
Regional constraint	o/e 1.12	unconstrained · MANE · 8,114 bp · p 0.039 · regional, not allelic
Overall
CADD	19.07	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

Grpmax group 0.00267% African / African-American · 2/75,024 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000125% 2/1,599,116 alleles · very rare exomes 1/1,446,842 · genomes 1/152,274 · 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.Pro102Ser
Coding: c.304C>T
MANE Select: NM_000551
dbSNP: rs532018719
Type: single nucleotide variant
Location: chr3:10142151 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 143 PDB
Residue 102: 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.Pro102Leu Uncertain significance ★★ ⚠ same residue
VHL p.Pro102= Benign/Likely benign ★★ same residue
VHL p.Pro102Arg Uncertain significance ★ ⚠ same residue
VHL p.Pro102Gln Uncertain significance ★ ⚠ same residue
VHL p.Pro102Thr Uncertain significance ★ ⚠ same residue
VHL p.Arg64Pro Pathogenic ★★★ same condition
VHL p.Asn78Ser Pathogenic ★★★ ⚠ same condition
VHL p.Glu70Ter 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-pro102ser (accessed [today's date]).

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