Is VHL p.Ser43= (c.129C>G) pathogenic?

VHL p.Ser43= (c.129C>G) is classified Likely benign in VHL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-27). Absent from gnomAD v4.1; Associated with Chuvash polycythemia.

What condition is associated with VHL p.Ser43= (c.129C>G)?

VHL p.Ser43= (c.129C>G) is associated with Chuvash polycythemia, von Hippel-Lindau disease (ClinVar).

How common is VHL p.Ser43= (c.129C>G) in the general population?

VHL p.Ser43= (c.129C>G) is absent from gnomAD v4.1 (gnomAD).

How is Chuvash erythrocytosis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

VHL p.Ser43=

c.129C>G · rs864622645 · VCV1618874

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Chuvash polycythemia

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 -2.4	GERP -2.6
Overall
CADD	4.624	PHRED · no single calibrated threshold — expert panels disagree

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.

Variant & gene context

Gene: VHL
Protein: p.Ser43=
Coding: c.129C>G
MANE Select: NM_000551
dbSNP: rs864622645
Type: single nucleotide variant
Location: chr3:10141976 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.45 · 143 PDB
Residue 43: the '8 x 5 aa tandem repeats of g-[pavg]-e-e-[daysle]' region; the 'disordered' region

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

For Chuvash erythrocytosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

VHL p.Ser43Pro Uncertain significance ★★ ⚠ same residue
VHL p.Ser43Cys Uncertain significance ★ ⚠ same residue
VHL p.Ser43Tyr 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-ser43 (accessed [today's date]).

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