Charcot-Marie-Tooth disease dominant intermediate F

Summary

Charcot-Marie-Tooth disease dominant intermediate F (MONDO:0014074) is a disease caused by GNB4 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GNB4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 257

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease dominant intermediate F
Mondo ID	MONDO:0014074
OMIM	615185
Orphanet	352670
DOID	DOID:0110206
UMLS	C4749463
MedGen	1666273
GARD	0009206
Is cancer (heuristic)	no

Also known as: autosomal dominant intermediate Charcot-Marie-Tooth disease type F · Charcot-Marie-Tooth disease dominant intermediate type F · Charcot-Marie-Tooth disease, dominant intermediate F · Charcot-Marie-Tooth disease, dominant Intermediate type F · CMTDIF · DI-CMTF · GNB4-related intermediate Charcot-Marie-Tooth neuropathy

Data availability: 257 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant intermediate Charcot-Marie-Tooth disease › Charcot-Marie-Tooth disease dominant intermediate F

Related subtypes (7): Charcot-Marie-Tooth disease dominant intermediate B, Charcot-Marie-Tooth Disease, axonal, type 2GG, Charcot-Marie-Tooth disease dominant intermediate D, Charcot-Marie-Tooth disease dominant intermediate C, Charcot-Marie-Tooth disease dominant intermediate E, autosomal dominant intermediate Charcot-Marie-Tooth disease with neuropathic pain, Charcot-Marie-Tooth disease, dominant intermediate A

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

257 retrieved; paginated sample, class counts are floors:

119 uncertain significance, 107 likely benign, 9 conflicting classifications of pathogenicity, 9 benign, 7 benign/likely benign, 3 likely pathogenic, 2 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
41941	NM_021629.4(GNB4):c.265A>G (p.Lys89Glu)	GNB4	Pathogenic	criteria provided, single submitter
488522	NM_021629.4(GNB4):c.229G>A (p.Gly77Arg)	GNB4	Pathogenic	criteria provided, multiple submitters, no conflicts
856439	NM_021629.4(GNB4):c.169A>G (p.Lys57Glu)	GNB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
41940	NM_021629.4(GNB4):c.158G>A (p.Gly53Asp)	GNB4	Likely pathogenic	criteria provided, single submitter
617599	NM_021629.4(GNB4):c.659A>G (p.Gln220Arg)	GNB4	Likely pathogenic	no assertion criteria provided
834350	NM_021629.4(GNB4):c.227A>G (p.Asp76Gly)	GNB4	Likely pathogenic	criteria provided, single submitter
1038672	NM_021629.4(GNB4):c.803A>G (p.Asn268Ser)	GNB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1098934	NM_021629.4(GNB4):c.918T>G (p.Gly306=)	GNB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1780732	NM_021629.4(GNB4):c.181A>T (p.Met61Leu)	GNB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2059644	NM_021629.4(GNB4):c.724G>A (p.Ala242Thr)	GNB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
540924	NM_021629.4(GNB4):c.204-4C>G	GNB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
572522	NM_021629.4(GNB4):c.44G>A (p.Arg15Gln)	GNB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
577411	NM_021629.4(GNB4):c.598G>A (p.Val200Ile)	GNB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
861762	NM_021629.4(GNB4):c.592A>T (p.Thr198Ser)	GNB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
956983	NM_021629.4(GNB4):c.709A>C (p.Asn237His)	GNB4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1001722	NM_021629.4(GNB4):c.265A>C (p.Lys89Gln)	GNB4	Uncertain significance	criteria provided, single submitter
1002904	NM_021629.4(GNB4):c.431-11_431-10del	GNB4	Uncertain significance	criteria provided, single submitter
1016177	NM_021629.4(GNB4):c.941G>A (p.Arg314His)	GNB4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1018608	NM_021629.4(GNB4):c.83C>G (p.Ala28Gly)	GNB4	Uncertain significance	criteria provided, single submitter
1025619	NM_021629.4(GNB4):c.125G>A (p.Arg42Gln)	GNB4	Uncertain significance	criteria provided, single submitter
1056355	NM_021629.4(GNB4):c.700-9C>G	GNB4	Uncertain significance	criteria provided, single submitter
1299242	NM_021629.4(GNB4):c.451T>G (p.Phe151Val)	GNB4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1348136	NM_021629.4(GNB4):c.916+3T>C	GNB4	Uncertain significance	criteria provided, single submitter
1364233	NM_021629.4(GNB4):c.915A>G (p.Ala305=)	GNB4	Uncertain significance	criteria provided, single submitter
1381047	NM_021629.4(GNB4):c.96+2T>C	GNB4	Uncertain significance	criteria provided, single submitter
1397286	NM_021629.4(GNB4):c.898C>G (p.Leu300Val)	GNB4	Uncertain significance	criteria provided, single submitter
1401220	NM_021629.4(GNB4):c.102del (p.Ser35fs)	GNB4	Uncertain significance	criteria provided, single submitter
1412291	NC_000003.11:g.(?179119001)(179138735_?)dup	GNB4	Uncertain significance	criteria provided, single submitter
1428077	NM_021629.4(GNB4):c.751C>T (p.Arg251Trp)	GNB4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1430690	NM_021629.4(GNB4):c.34G>C (p.Glu12Gln)	GNB4	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
GNB4	Strong	Autosomal dominant	Charcot-Marie-Tooth disease dominant intermediate F	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GNB4	Orphanet:352670	Autosomal dominant intermediate Charcot-Marie-Tooth disease type F

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GNB4	HGNC:20731	ENSG00000114450	Q9HAV0	Guanine nucleotide-binding protein subunit beta-4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GNB4	Guanine nucleotide-binding protein subunit beta-4	Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Scaffold/PPI	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GNB4	Scaffold/PPI	no		WD40_G-protein_beta-like, WD40_rpt, WD40/YVTN_repeat-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
secondary oocyte	1
upper arm skin	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GNB4	258	ubiquitous	marker	upper arm skin, secondary oocyte, upper leg skin

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GNB4	3,343

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GNB4	Q9HAV0	97.14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
G beta:gamma signalling through BTK	1	634.4×	0.005	GNB4
Prostacyclin signalling through prostacyclin receptor	1	601.0×	0.005	GNB4
G beta:gamma signalling through PLC beta	1	571.0×	0.005	GNB4
G beta:gamma signalling through CDC42	1	571.0×	0.005	GNB4
Presynaptic function of Kainate receptors	1	543.8×	0.005	GNB4
ADP signalling through P2Y purinoceptor 12	1	496.5×	0.005	GNB4
G-protein activation	1	475.8×	0.005	GNB4
Thromboxane signalling through TP receptor	1	475.8×	0.005	GNB4
ADP signalling through P2Y purinoceptor 1	1	456.8×	0.005	GNB4
G beta:gamma signalling through PI3Kgamma	1	439.2×	0.005	GNB4
Activation of G protein gated Potassium channels	1	393.8×	0.005	GNB4
Adrenaline,noradrenaline inhibits insulin secretion	1	393.8×	0.005	GNB4
Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits	1	393.8×	0.005	GNB4
Thrombin signalling through proteinase activated receptors (PARs)	1	356.9×	0.005	GNB4
Glucagon signaling in metabolic regulation	1	346.1×	0.005	GNB4
Glucagon-type ligand receptors	1	346.1×	0.005	GNB4
Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding	1	300.5×	0.006	GNB4
Glucagon-like Peptide-1 (GLP1) regulates insulin secretion	1	265.6×	0.006	GNB4
Vasopressin regulates renal water homeostasis via Aquaporins	1	265.6×	0.006	GNB4
ADORA2B mediated anti-inflammatory cytokines production	1	253.8×	0.006	GNB4
GPER1 signaling	1	248.3×	0.006	GNB4
G alpha (z) signalling events	1	233.1×	0.006	GNB4
Ca2+ pathway	1	178.4×	0.007	GNB4
Extra-nuclear estrogen signaling	1	170.4×	0.007	GNB4
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	160.8×	0.007	GNB4
G alpha (12/13) signalling events	1	137.6×	0.008	GNB4
G alpha (s) signalling events	1	73.2×	0.015	GNB4
G alpha (q) signalling events	1	57.4×	0.018	GNB4
G alpha (i) signalling events	1	39.0×	0.026	GNB4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
substantia nigra development	1	366.4×	0.005	GNB4
G protein-coupled receptor signaling pathway	1	36.2×	0.028	GNB4

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GNB4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	GNB4

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
GNB4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.