Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;

Summary

Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b; (MONDO:0014906) is a disease caused by MFN2 (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Causal gene: MFN2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 51
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;
Mondo ID	MONDO:0014906
OMIM	617087
DOID	DOID:0111557
NCIT	C150647
UMLS	C4310725
MedGen	934692
GARD	0025032
Is cancer (heuristic)	no

Also known as: Charcot-Marie-Tooth disease type 2A2B · CMT2A2B

Data availability: 51 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › hereditary peripheral neuropathy › Charcot-Marie-Tooth disease › Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;

Related subtypes (23): Charcot-Marie-Tooth disease, Guadalajara neuronal type, Charcot-Marie-Tooth disease with ptosis and parkinsonism, Charcot-Marie-Tooth disease type 3, neuronopathy, distal hereditary motor, autosomal dominant 1, neuropathy, hereditary motor and sensory, type 6A, demyelinating hereditary motor and sensory neuropathy, intermediate Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 2, Charcot-Marie-Tooth disease type X, Charcot-Marie-Tooth disease type 4, Charcot-Marie-Tooth disease type 1, Charcot-Marie-Tooth disease, axonal, mitochondrial form, 1, Charcot-Marie-Tooth disease, axonal, type 2FF, Charcot-Marie-Tooth disease, axonal, Type 2HH, Charcot-Marie-Tooth disease, demyelinating, IIA 1I, Charcot-Marie-Tooth disease, demyelinating, IIA 1H, Charcot-Marie-Tooth disease, axonal, IIa 2II, Charcot-Marie-Tooth disease, demyelinating, type 1G, Charcot-Marie-Tooth disease, demyelinating, type 1J, Charcot-Marie-tooth disease, axonal, type 2JJ, Charcot-Marie-Tooth disease, axonal, type 2KK, Charcot-Marie-Tooth disease, axonal, type 2LL, charcot-marie-tooth disease, axonal, type 2MM

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

51 retrieved; paginated sample, class counts are floors:

15 uncertain significance, 14 conflicting classifications of pathogenicity, 8 pathogenic, 5 benign/likely benign, 5 pathogenic/likely pathogenic, 3 likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1703243	NM_014874.4(MFN2):c.600-31T>G	MFN2	Pathogenic	criteria provided, single submitter
2268	NM_014874.4(MFN2):c.281G>A (p.Arg94Gln)	MFN2	Pathogenic	criteria provided, multiple submitters, no conflicts
2269	NM_014874.4(MFN2):c.2219G>C (p.Trp740Ser)	MFN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2271	NM_014874.4(MFN2):c.839G>A (p.Arg280His)	MFN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2276	NM_014874.4(MFN2):c.280C>T (p.Arg94Trp)	MFN2	Pathogenic	criteria provided, multiple submitters, no conflicts
2280	NM_014874.4(MFN2):c.2119C>T (p.Arg707Trp)	MFN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2281	NM_014874.4(MFN2):c.310C>T (p.Arg104Trp)	MFN2	Pathogenic	criteria provided, multiple submitters, no conflicts
30736	NM_014874.4(MFN2):c.647T>C (p.Phe216Ser)	MFN2	Pathogenic	criteria provided, multiple submitters, no conflicts
30737	NM_014874.3:c.600_816del	MFN2	Pathogenic	no assertion criteria provided
30738	NM_014874.4(MFN2):c.1085C>T (p.Thr362Met)	MFN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3376754	NM_014874.4(MFN2):c.1817del (p.Gly606fs)	MFN2	Pathogenic	criteria provided, single submitter
3382575	NM_014874.4(MFN2):c.1822_1826dup (p.Leu610fs)	MFN2	Pathogenic	criteria provided, single submitter
587402	NM_014874.4(MFN2):c.334G>A (p.Val112Met)	MFN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2882121	NM_014874.4(MFN2):c.2170C>A (p.Leu724Ile)	MFN2	Likely pathogenic	criteria provided, single submitter
543243	NM_014874.4(MFN2):c.1160+1G>A	MFN2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
549684	NM_014874.4(MFN2):c.154G>A (p.Glu52Lys)	MFN2	Likely pathogenic	no assertion criteria provided
1806999	NM_014874.4(MFN2):c.2120G>A (p.Arg707Gln)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214642	NM_014874.4(MFN2):c.842G>C (p.Cys281Ser)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214653	NM_014874.4(MFN2):c.749G>A (p.Arg250Gln)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
243074	NM_014874.4(MFN2):c.526G>A (p.Gly176Ser)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
30734	NM_014874.4(MFN2):c.107AGA[2] (p.Lys38del)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3896911	NM_014874.4(MFN2):c.785C>T (p.Ala262Val)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
420586	NM_014874.4(MFN2):c.2230G>A (p.Glu744Lys)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
439898	NM_014874.4(MFN2):c.1101G>C (p.Gln367His)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
543219	NM_014874.4(MFN2):c.748C>T (p.Arg250Trp)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
549683	NM_014874.4(MFN2):c.404G>A (p.Arg135Gln)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
581439	NM_014874.4(MFN2):c.271G>T (p.Val91Leu)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
637433	NM_014874.4(MFN2):c.2258dup (p.Gln754fs)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
637936	NM_014874.4(MFN2):c.322G>A (p.Gly108Arg)	MFN2	Conflicting classifications of pathogenicity	no assertion criteria provided
999667	NM_014874.4(MFN2):c.2232G>T (p.Glu744Asp)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 5 · 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
MFN2	Definitive	Semidominant	axonal hereditary motor and sensory neuropathy	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MFN2	Orphanet:2398	Multiple symmetric lipomatosis
MFN2	Orphanet:64751	Hereditary motor and sensory neuropathy type 5
MFN2	Orphanet:90118	Severe early-onset axonal neuropathy due to MFN2 deficiency
MFN2	Orphanet:90120	Hereditary motor and sensory neuropathy type 6
MFN2	Orphanet:99947	Autosomal dominant Charcot-Marie-Tooth disease type 2A2

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
MFN2	HGNC:16877	ENSG00000116688	O95140	Mitofusin-2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MFN2	Mitofusin-2	Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion.

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)
MFN2	Other/Unknown	no		Fzo/mitofusin_HR2, Mitofusin_fam, P-loop_NTPase

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
apex of heart	1
cardiac ventricle	1
heart left ventricle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MFN2	297	ubiquitous	marker	apex of heart, heart left ventricle, cardiac ventricle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MFN2	3,853

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MFN2	O95140	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Miro GTPase Cycle	1	2284.0×	0.003	MFN2
RHOT2 GTPase cycle	1	1631.4×	0.003	MFN2
Mitophagy	1	1038.2×	0.004	MFN2
PINK1-PRKN Mediated Mitophagy	1	356.9×	0.008	MFN2
Selective autophagy	1	278.5×	0.008	MFN2
Autophagy	1	148.3×	0.012	MFN2
Macroautophagy	1	115.3×	0.014	MFN2
Factors involved in megakaryocyte development and platelet production	1	66.4×	0.021	MFN2
Hemostasis	1	36.0×	0.033	MFN2
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	33.5×	0.033	MFN2
Signal Transduction	1	10.2×	0.098	MFN2

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
type 2 mitophagy	1	3370.4×	0.002	MFN2
mitochondrial membrane organization	1	2407.4×	0.002	MFN2
positive regulation of vascular associated smooth muscle cell apoptotic process	1	2106.5×	0.002	MFN2
mitochondrion localization	1	1685.2×	0.002	MFN2
protein localization to phagophore assembly site	1	991.3×	0.003	MFN2
mitochondrial fusion	1	842.6×	0.003	MFN2
blastocyst formation	1	766.0×	0.003	MFN2
camera-type eye morphogenesis	1	766.0×	0.003	MFN2
negative regulation of Ras protein signal transduction	1	674.1×	0.003	MFN2
negative regulation of smooth muscle cell proliferation	1	624.1×	0.003	MFN2
obsolete protein targeting to mitochondrion	1	581.1×	0.003	MFN2
positive regulation of vascular associated smooth muscle cell proliferation	1	432.1×	0.003	MFN2
response to unfolded protein	1	300.9×	0.004	MFN2
aerobic respiration	1	247.8×	0.005	MFN2
positive regulation of cold-induced thermogenesis	1	163.6×	0.007	MFN2
apoptotic process	1	28.7×	0.035	MFN2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MFN2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MFN2	3	Binding:3

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	MFN2

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)
MFN2	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05902351	Not specified	RECRUITING	Natural History Study for Charcot Marie Tooth Disease