Is VHL p.Pro95Ser (c.283C>T) pathogenic?

VHL p.Pro95Ser (c.283C>T) is classified Uncertain significance in VHL (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-16). AlphaMissense: likely pathogenic (0.7234); No allele count reported in gnomAD v4.1 (AN 1,600,744); Associated with von Hippel-Lindau disease.

What condition is associated with VHL p.Pro95Ser (c.283C>T)?

VHL p.Pro95Ser (c.283C>T) is associated with von Hippel-Lindau disease, Chuvash polycythemia (ClinVar).

How common is VHL p.Pro95Ser (c.283C>T) in the general population?

VHL p.Pro95Ser (c.283C>T) is no allele count reported in gnomAD v4.1 (AN 1,600,744) (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.Pro95Ser (c.283C>T)?

AlphaMissense predicts likely pathogenic (score 0.7234) — an in-silico prediction, not a clinical call.

VHL p.Pro95Ser

c.283C>T · rs1376530057 · VCV661136

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7234 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,600,744)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

von Hippel-Lindau disease

Computational evidence

Protein change
AlphaMissense	0.7234	likely pathogenic
REVEL	0.725	pathogenic-leaning
SaProt	LLR -10.33	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.1	GERP 0.54, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 8,114 bp · p 0.039 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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 1,600,744). 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.Pro95Ser
Coding: c.283C>T
MANE Select: NM_000551
dbSNP: rs1376530057
Type: single nucleotide variant
Location: chr3:10142130 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 143 PDB
Residue 95: a β-strand; a UniProt-annotated variant site (in vhld; type i)

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

For Von Hippel-Lindau disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 100 000 (United Kingdom)

Similar variants

VHL p.Pro95Leu Uncertain significance ★★ ⚠ same residue
VHL p.Pro95= Benign/Likely benign ★★ same residue
VHL p.Pro95Arg Uncertain significance ★ ⚠ 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-pro95ser (accessed [today's date]).

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