Is GNB4 p.Ser67Phe (c.200C>T) pathogenic?

GNB4 p.Ser67Phe (c.200C>T) is classified Uncertain significance in GNB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-10). AlphaMissense: likely pathogenic (0.9154); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease dominant intermediate F.

What condition is associated with GNB4 p.Ser67Phe (c.200C>T)?

GNB4 p.Ser67Phe (c.200C>T) is associated with Charcot-Marie-Tooth disease dominant intermediate F (ClinVar).

How common is GNB4 p.Ser67Phe (c.200C>T) in the general population?

GNB4 p.Ser67Phe (c.200C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GNB4 p.Ser67Phe (c.200C>T)?

AlphaMissense predicts likely pathogenic (score 0.9154) — an in-silico prediction, not a clinical call.

GNB4 p.Ser67Phe

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.200C>T · rs2473915534 · VCV2740311

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9154 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Charcot-Marie-Tooth disease dominant intermediate F

Computational evidence

Protein change
AlphaMissense	0.9154	likely pathogenic
REVEL	0.61	indeterminate
SaProt	LLR -15.21	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 25 kb · p 4.2e-07 · regional, not allelic
Overall
CADD	32.0	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

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.Ser67Phe
Coding: c.200C>T
MANE Select: NM_021629
dbSNP: rs2473915534
Type: single nucleotide variant
Location: chr3:179419402 (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.Ser67= Uncertain significance ★ same residue
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

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-ser67phe (accessed [today's date]).

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