Is GNB4 p.Ser227= (c.681A>G) pathogenic?

GNB4 p.Ser227= (c.681A>G) is classified Likely benign in GNB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-07-22). Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease dominant intermediate F.

What condition is associated with GNB4 p.Ser227= (c.681A>G)?

GNB4 p.Ser227= (c.681A>G) is associated with Charcot-Marie-Tooth disease dominant intermediate F (ClinVar).

How common is GNB4 p.Ser227= (c.681A>G) in the general population?

GNB4 p.Ser227= (c.681A>G) is absent from gnomAD v4.1 (gnomAD).

GNB4 p.Ser227=

Q: How is Autosomal dominant intermediate Charcot-Marie-Tooth disease type F inherited?

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

c.681A>G · rs2108589151 · VCV1141736

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Charcot-Marie-Tooth disease dominant intermediate F

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.034	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -4.3, phastCons 0.002
Overall
CADD	6.479	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: GNB4
Protein: p.Ser227=
Coding: c.681A>G
MANE Select: NM_021629
dbSNP: rs2108589151
Type: single nucleotide variant
Location: chr3:179413430 (GRCh38)
Gene constraint: LOEUF 0.863 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 97.14

Full GNB4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease dominant intermediate F — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant intermediate Charcot-Marie-Tooth disease type F (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

GNB4 p.Gly77Arg Pathogenic ★★ same condition
GNB4 p.Lys57Glu Pathogenic/Likely pathogenic ★★ same condition
GNB4 c.497+1G>C Uncertain significance ★★ same condition
GNB4 p.Arg137Ter Uncertain significance ★★ same condition
GNB4 p.Arg15Trp Uncertain significance ★★ ⚠ same condition
GNB4 p.Arg214Ter Uncertain significance ★★ same condition
GNB4 p.Arg22Gln Uncertain significance ★★ ⚠ same condition
GNB4 p.Arg251Gln Uncertain significance ★★ ⚠ 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/gnb4-p-ser227 (accessed [today's date]).

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