Is GNB4 p.Arg283Pro (c.848G>C) pathogenic?

GNB4 p.Arg283Pro (c.848G>C) is classified Uncertain significance in GNB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-11). AlphaMissense: likely pathogenic (0.9985); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease dominant intermediate F.

What condition is associated with GNB4 p.Arg283Pro (c.848G>C)?

GNB4 p.Arg283Pro (c.848G>C) is associated with Charcot-Marie-Tooth disease dominant intermediate F (ClinVar).

How common is GNB4 p.Arg283Pro (c.848G>C) in the general population?

GNB4 p.Arg283Pro (c.848G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GNB4 p.Arg283Pro (c.848G>C)?

AlphaMissense predicts likely pathogenic (score 0.9985) — an in-silico prediction, not a clinical call.

GNB4 p.Arg283Pro

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.848G>C · rs186593898 · VCV408271

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9985 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease dominant intermediate F

Computational evidence

Protein change
AlphaMissense	0.9985	likely pathogenic
REVEL	0.651	pathogenic-leaning
SaProt	LLR -18.15	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 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 25 kb · p 4.2e-07 · regional, not allelic
Overall
CADD	26.1	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.Arg283Pro
Coding: c.848G>C
MANE Select: NM_021629
dbSNP: rs186593898
Type: single nucleotide variant
Location: chr3:179405258 (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.Arg283Cys Uncertain significance ★ ⚠ same residue
GNB4 p.Arg283His 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

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-arg283pro (accessed [today's date]).

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