Charcot-Marie-Tooth Disease, axonal, type 2GG

Summary

Charcot-Marie-Tooth Disease, axonal, type 2GG (MONDO:0011675) is a disease caused by GBF1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GBF1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 24

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		20	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth Disease, axonal, type 2GG
Mondo ID	MONDO:0011675
MeSH	C564702
OMIM	606483
Orphanet	100043
DOID	DOID:0110202
SNOMED CT	765744006
UMLS	C5561933
MedGen	1794143
GARD	0012437
Is cancer (heuristic)	no

Also known as: autosomal dominant intermediate Charcot-Marie-Tooth disease type A · Charcot-Marie-Tooth disease dominant intermediate type A · Charcot-Marie-Tooth disease, dominant intermediate A · CMT2GG · CMTDIA

Data availability: 24 ClinVar variants · 1 GenCC gene-disease record.

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, axonal, type 2GG

Related subtypes (7): Charcot-Marie-Tooth disease dominant intermediate B, Charcot-Marie-Tooth disease dominant intermediate D, Charcot-Marie-Tooth disease dominant intermediate C, Charcot-Marie-Tooth disease dominant intermediate E, Charcot-Marie-Tooth disease dominant intermediate F, 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

24 retrieved; paginated sample, class counts are floors:

20 uncertain significance, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
972904	NM_001377137.1(GBF1):c.4385G>A (p.Arg1462Gln)	GBF1	Pathogenic/Likely pathogenic	no assertion criteria provided
972907	NM_001377137.1(GBF1):c.2948G>A (p.Cys983Tyr)	GBF1	Pathogenic/Likely pathogenic	no assertion criteria provided
973612	NM_001377137.1(GBF1):c.3528G>A (p.Trp1176Ter)	GBF1	Pathogenic/Likely pathogenic	no assertion criteria provided
975152	NM_001377137.1(GBF1):c.3413C>T (p.Ala1138Val)	GBF1	Pathogenic/Likely pathogenic	no assertion criteria provided
1342026	NM_001377137.1(GBF1):c.4278T>A (p.Ser1426Arg)	GBF1	Uncertain significance	criteria provided, single submitter
1521842	NM_001377137.1(GBF1):c.2732_2733del (p.Pro911fs)	GBF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1697221	NM_001377137.1(GBF1):c.5294G>C (p.Gly1765Ala)	GBF1	Uncertain significance	criteria provided, single submitter
1699409	NM_001377137.1(GBF1):c.5501C>T (p.Ala1834Val)	GBF1	Uncertain significance	criteria provided, single submitter
2350045	NM_001377137.1(GBF1):c.562A>G (p.Met188Val)	GBF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2401069	NM_001377137.1(GBF1):c.3412G>A (p.Ala1138Thr)	GBF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3065522	NM_001377137.1(GBF1):c.3499G>A (p.Glu1167Lys)	GBF1	Uncertain significance	criteria provided, single submitter
3236643	NM_001377137.1(GBF1):c.556G>C (p.Val186Leu)	GBF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3251941	NM_001377137.1(GBF1):c.4494C>T (p.Asp1498=)	GBF1	Uncertain significance	criteria provided, single submitter
3280899	NM_001377137.1(GBF1):c.2899G>A (p.Ala967Thr)	GBF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3340094	NM_001377137.1(GBF1):c.1421A>G (p.Tyr474Cys)	GBF1	Uncertain significance	criteria provided, single submitter
3731409	NM_001377137.1(GBF1):c.520A>G (p.Ser174Gly)	GBF1	Uncertain significance	criteria provided, single submitter
3896874	NM_001377137.1(GBF1):c.1436G>A (p.Arg479Gln)	GBF1	Uncertain significance	criteria provided, single submitter
3899271	NM_001377137.1(GBF1):c.1229G>T (p.Arg410Leu)	GBF1	Uncertain significance	criteria provided, single submitter
3902839	NM_001377137.1(GBF1):c.3538C>T (p.Arg1180Ter)	GBF1	Uncertain significance	criteria provided, single submitter
4073427	NM_001377137.1(GBF1):c.2439T>G (p.Cys813Trp)	GBF1	Uncertain significance	no assertion criteria provided
4078746	NM_001377137.1(GBF1):c.1460G>C (p.Ser487Thr)	GBF1	Uncertain significance	criteria provided, single submitter
4078747	NM_001377137.1(GBF1):c.5521C>T (p.Pro1841Ser)	GBF1	Uncertain significance	criteria provided, single submitter
4278408	NM_001377137.1(GBF1):c.2696A>G (p.Tyr899Cys)	GBF1	Uncertain significance	criteria provided, single submitter
4292554	NM_001377137.1(GBF1):c.4776+82A>G	GBF1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 0 · 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
GBF1	Strong	Autosomal dominant	Charcot-Marie-Tooth Disease, axonal, type 2GG	2

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
GBF1	HGNC:4181	ENSG00000107862	Q92538	Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GBF1	Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1	Guanine-nucleotide exchange factor (GEF) for members of the Arf family of small GTPases involved in trafficking in the early secretory pathway; its GEF activity initiates the coating of nascent vesicles via the localized generation of acti…

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GBF1	Other/Unknown	no		Sec7_dom, ARM-type_fold, Sec7_C_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
adenohypophysis	1
colonic epithelium	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GBF1	259	ubiquitous	marker	colonic epithelium, ventricular zone, adenohypophysis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GBF1	2,436

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GBF1	Q92538	71.42

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Assembly and Release of Dengue Virus Virions	1	1427.5×	0.004	GBF1
VxPx cargo-targeting to cilium	1	519.1×	0.006	GBF1
trans-Golgi Network Vesicle Budding	1	253.8×	0.008	GBF1
COPI-dependent Golgi-to-ER retrograde traffic	1	110.9×	0.011	GBF1
COPI-mediated anterograde transport	1	109.8×	0.011	GBF1
Dengue Virus-Host Interactions	1	45.7×	0.022	GBF1

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
cell activation involved in immune response	1	16852.0×	7e-04	GBF1
protein localization to endoplasmic reticulum tubular network	1	16852.0×	7e-04	GBF1
establishment of monopolar cell polarity	1	8426.0×	7e-04	GBF1
endoplasmic reticulum-Golgi intermediate compartment organization	1	8426.0×	7e-04	GBF1
Golgi disassembly	1	2808.7×	0.001	GBF1
COPI coating of Golgi vesicle	1	2407.4×	0.001	GBF1
protein localization to endoplasmic reticulum exit site	1	2106.5×	0.001	GBF1
reactive oxygen species biosynthetic process	1	1872.4×	0.001	GBF1
regulation of protein localization to cell surface	1	1685.2×	0.001	GBF1
post-Golgi vesicle-mediated transport	1	1053.2×	0.002	GBF1
Golgi to endosome transport	1	1053.2×	0.002	GBF1
regulation of ARF protein signal transduction	1	887.0×	0.002	GBF1
protein localization to Golgi apparatus	1	802.5×	0.002	GBF1
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	1	337.0×	0.005	GBF1
neutrophil chemotaxis	1	285.6×	0.005	GBF1
regulation of mitotic cell cycle	1	240.7×	0.006	GBF1
retrograde transport, endosome to Golgi	1	205.5×	0.006	GBF1
cellular response to virus	1	200.6×	0.006	GBF1
endoplasmic reticulum to Golgi vesicle-mediated transport	1	135.9×	0.008	GBF1
Golgi organization	1	133.8×	0.008	GBF1
cilium assembly	1	73.6×	0.014	GBF1
protein transport	1	43.9×	0.023	GBF1

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
GBF1	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	GBF1

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)
GBF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.