Is VHL p.Ser72Phe (c.215C>T) pathogenic?

VHL p.Ser72Phe (c.215C>T) is classified Uncertain significance in VHL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-07). AlphaMissense: likely pathogenic (0.9648); Very rare (popmax 0.00133%, afr); Associated with Chuvash polycythemia.

What condition is associated with VHL p.Ser72Phe (c.215C>T)?

VHL p.Ser72Phe (c.215C>T) is associated with Chuvash polycythemia, von Hippel-Lindau disease, hereditary neoplastic syndrome (ClinVar).

How common is VHL p.Ser72Phe (c.215C>T) in the general population?

VHL p.Ser72Phe (c.215C>T) is very rare (popmax 0.00133%, afr) (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.Ser72Phe (c.215C>T)?

AlphaMissense predicts likely pathogenic (score 0.9648) — an in-silico prediction, not a clinical call.

VHL p.Ser72Phe

c.215C>T · rs962558566 · VCV864054

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9648 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Chuvash polycythemia

Computational evidence

Protein change
AlphaMissense	0.9648	likely pathogenic
REVEL	0.614	indeterminate
SaProt	LLR -12.13	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 0.71, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 8,114 bp · p 0.039 · regional, not allelic
Overall
CADD	24.0	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

Grpmax group 0.00133% African / African-American · 1/75,006 alleles

Overall 0.000124% 2/1,607,220 alleles · very rare exomes 2/1,454,896 · genomes 0/152,324 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,006
South Asian	0.0011%	90,714

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.Ser72Phe
Coding: c.215C>T
MANE Select: NM_000551
dbSNP: rs962558566
Type: single nucleotide variant
Location: chr3:10142062 (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

Chuvash polycythemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: von Hippel-Lindau disease hereditary neoplastic syndrome

For Chuvash erythrocytosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

VHL p.Ser72Pro Pathogenic/Likely pathogenic ★★ 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-ser72phe (accessed [today's date]).

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