Is VHL p.Ser72Pro (c.214T>C) pathogenic?

VHL p.Ser72Pro (c.214T>C) is classified Pathogenic/Likely pathogenic in VHL (ClinVar, Multiple submitters, 4 submitters; last evaluated 2020-12-01). AlphaMissense: likely pathogenic (0.9791); Absent from gnomAD v4.1; Associated with von Hippel-Lindau disease.

What condition is associated with VHL p.Ser72Pro (c.214T>C)?

VHL p.Ser72Pro (c.214T>C) is associated with von Hippel-Lindau disease, Chuvash polycythemia, hereditary neoplastic syndrome (ClinVar).

How common is VHL p.Ser72Pro (c.214T>C) in the general population?

VHL p.Ser72Pro (c.214T>C) is absent from gnomAD v4.1 (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.Ser72Pro (c.214T>C)?

AlphaMissense predicts likely pathogenic (score 0.9791) — an in-silico prediction, not a clinical call.

VHL p.Ser72Pro

c.214T>C · rs869025618 · VCV223163

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9791 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

von Hippel-Lindau disease

Computational evidence

Protein change
AlphaMissense	0.9791	likely pathogenic ✓ concordant with ClinVar
REVEL	0.725	pathogenic-leaning
SaProt	LLR -12.21	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 0.51, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 8,114 bp · p 0.039 · regional, not allelic
Overall
CADD	22.5	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.

Cancer therapy — CIViC

Disease	Therapies	Level	Significance
Von Hippel-Lindau Disease		C	Predisposition
Von Hippel-Lindau Disease		C	Predisposition

Variant & gene context

Gene: VHL
Protein: p.Ser72Pro
Coding: c.214T>C
MANE Select: NM_000551
dbSNP: rs869025618
Type: single nucleotide variant
Location: chr3:10142061 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 143 PDB
Residue 72: 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 hereditary neoplastic syndrome

For Von Hippel-Lindau disease (Orphanet):

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

Similar variants

VHL p.Ser72Phe Uncertain significance ★★ ⚠ same residue
VHL p.Ser72= Conflicting classifications of pathogenicity ★ same residue
VHL p.Ser72fs Pathogenic ★ same residue
VHL p.Ser72del 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

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-ser72pro (accessed [today's date]).

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