Is GNB4 p.Phe241= (c.723C>T) pathogenic?

GNB4 p.Phe241= (c.723C>T) is classified Likely benign in GNB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-24). Ultra-rare (popmax 0.0165%, mid); Associated with Charcot-Marie-Tooth disease dominant intermediate F.

What condition is associated with GNB4 p.Phe241= (c.723C>T)?

GNB4 p.Phe241= (c.723C>T) is associated with Charcot-Marie-Tooth disease dominant intermediate F (ClinVar).

How common is GNB4 p.Phe241= (c.723C>T) in the general population?

GNB4 p.Phe241= (c.723C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

GNB4 p.Phe241=

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.723C>T · rs752815541 · VCV1631004

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

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.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.33 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.3	GERP -4.3, phastCons 1
Overall
CADD	9.671	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,074 alleles

Filtering AF 0.00816% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00634%

Overall 0.00198% 32/1,612,548 alleles · ultra-rare exomes 28/1,460,342 · genomes 4/152,206 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,074
African / African-American	0.0147%	6,808
Remaining individualsnot grpmax-eligible	0.00961%	10,407
European (non-Finnish)	0.00119%	84,211

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: GNB4
Protein: p.Phe241=
Coding: c.723C>T
MANE Select: NM_021629
dbSNP: rs752815541
Type: single nucleotide variant
Location: chr3:179405383 (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-phe241 (accessed [today's date]).

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