Charcot-Marie-Tooth disease type 2A1

Summary

Charcot-Marie-Tooth disease type 2A1 (MONDO:0007308) is a disease with 3 cohort genes and 3 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 107
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

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

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease type 2A1
Mondo ID	MONDO:0007308
MeSH	C566138
OMIM	118210
Orphanet	99946
DOID	DOID:0110154
ICD-11	2087067372
NCIT	C134952, C150609
SNOMED CT	717016001
UMLS	C1861678
MedGen	350076
GARD	0001248
Is cancer (heuristic)	no

Also known as: Charcot Marie Tooth disease type 2A · Charcot-Marie-Tooth disease type 2 caused by mutation in KIF1B · Charcot-Marie-Tooth disease type 2A · Charcot-Marie-Tooth disease type 2A1 · Charcot-Marie-Tooth disease, axonal, type 2A · Charcot-Marie-Tooth disease, axonal, type 2A1 · Charcot-Marie-Tooth disease, neuronal, type 2A · Charcot-Marie-Tooth disease, type 2A1 · CMT 2A · CMT2A · CMT2A1 · hereditary motor and sensory neuropathy 2 A · hereditary motor and sensory neuropathy IIA1 · HMSN IIA · HMSN IIA1 · HMSN2A1 · KIF1B Charcot-Marie-Tooth disease type 2

Data availability: 107 ClinVar variants · 5 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 type 2 › Charcot-Marie-Tooth disease type 2A1

Related subtypes (37): Charcot-Marie-Tooth disease type 2B, Charcot-Marie-Tooth disease type 2D, Charcot-Marie-Tooth disease type 2B1, Charcot-Marie-Tooth disease type 2B2, Charcot-Marie-Tooth disease axonal type 2C, Charcot-Marie-Tooth disease axonal type 2F, Charcot-Marie-Tooth disease type 2I, Charcot-Marie-Tooth disease type 2E, Charcot-Marie-Tooth disease axonal type 2H, Charcot-Marie-Tooth disease type 2J, Charcot-Marie-Tooth disease axonal type 2K, Charcot-Marie-Tooth disease axonal type 2L, Charcot-Marie-Tooth disease type 2A2, giant axonal neuropathy 2, Charcot-Marie-Tooth disease axonal type 2N, Charcot-Marie-Tooth disease axonal type 2O, Charcot-Marie-Tooth disease axonal type 2P, Charcot-Marie-Tooth disease axonal type 2Q, Charcot-Marie-Tooth disease type 2R, Charcot-Marie-Tooth disease axonal type 2S, Charcot-Marie-Tooth disease axonal type 2U, Charcot-Marie-Tooth disease axonal type 2V, autosomal dominant Charcot-Marie-Tooth disease type 2W, Charcot-Marie-Tooth disease axonal type 2X, Charcot-Marie-Tooth disease type 2Y, Charcot-Marie-Tooth disease axonal type 2Z, Charcot-Marie-Tooth disease axonal type 2CC, autosomal dominant Charcot-Marie-Tooth disease type 2M, Charcot-Marie-Tooth disease type 2B5, autosomal dominant Charcot-Marie-Tooth disease type 2 due to KIF5A mutation, autosomal dominant Charcot-Marie-Tooth disease type 2 due to TFG mutation, autosomal dominant Charcot-Marie-Tooth disease type 2K, Charcot-Marie-Tooth disease, axonal, type 2EE, autosomal dominant charcot-marie-tooth disease type 2 due to DGAT2 mutation, Charcot-Marie-Tooth disease type 2T, MME-related autosomal dominant Charcot Marie Tooth disease type 2, Charcot-Marie-tooth disease, axonal, type 2DD

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

107 retrieved; paginated sample, class counts are floors:

75 uncertain significance, 21 conflicting classifications of pathogenicity, 5 benign, 4 benign/likely benign, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4526336	NM_001365951.3(KIF1B):c.1036A>T (p.Arg346Ter)	KIF1B	Pathogenic	criteria provided, single submitter
4658	NM_001365951.3(KIF1B):c.293A>T (p.Gln98Leu)	KIF1B	Pathogenic	no assertion criteria provided
1007653	NM_001365951.3(KIF1B):c.4970C>T (p.Ala1657Val)	KIF1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1284949	NM_001365951.3(KIF1B):c.2115+6581G>A	KIF1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1419477	NM_001365951.3(KIF1B):c.4445G>A (p.Arg1482Gln)	KIF1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
155749	NM_001365951.3(KIF1B):c.3407T>C (p.Ile1136Thr)	KIF1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
157531	NM_001365951.3(KIF1B):c.899A>G (p.Lys300Arg)	KIF1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1744917	NM_001365951.3(KIF1B):c.5173G>A (p.Val1725Ile)	KIF1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2712316	NM_001365951.3(KIF1B):c.184-6T>G	KIF1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291582	NM_001365951.3(KIF1B):c.4820G>A (p.Cys1607Tyr)	KIF1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3533871	NM_001365951.3(KIF1B):c.4056G>A (p.Arg1352=)	KIF1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3891480	NM_001365951.3(KIF1B):c.2115+6523G>A	KIF1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
408312	NM_001365951.3(KIF1B):c.2159C>T (p.Thr720Ile)	KIF1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4660	NM_001365951.3(KIF1B):c.2618C>T (p.Thr873Ile)	KIF1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
476776	NM_001365951.3(KIF1B):c.1364C>T (p.Thr455Met)	KIF1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
476778	NM_001365951.3(KIF1B):c.1594C>G (p.Pro532Ala)	KIF1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
476788	NM_001365951.3(KIF1B):c.5214C>G (p.Asp1738Glu)	KIF1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
570523	NM_001365951.3(KIF1B):c.2675+3A>G	KIF1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
843328	NM_001365951.3(KIF1B):c.1770C>G (p.Ser590Arg)	KIF1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
855407	NM_001365951.3(KIF1B):c.5203A>G (p.Ser1735Gly)	KIF1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
875167	NM_001365951.3(KIF1B):c.4282G>A (p.Gly1428Ser)	KIF1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
943303	NM_001365951.3(KIF1B):c.392A>G (p.Asn131Ser)	KIF1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
946995	NM_001365951.3(KIF1B):c.4297C>A (p.Pro1433Thr)	KIF1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2582694	NM_032564.5(DGAT2):c.245T>C (p.Val82Ala)	DGAT2	Uncertain significance	no assertion criteria provided
1018792	NM_001365951.3(KIF1B):c.3650G>A (p.Arg1217His)	KIF1B	Uncertain significance	criteria provided, multiple submitters, no conflicts
1032652	NM_001365951.3(KIF1B):c.3434G>A (p.Arg1145His)	KIF1B	Uncertain significance	criteria provided, multiple submitters, no conflicts
1062967	NM_001365951.3(KIF1B):c.5260T>G (p.Tyr1754Asp)	KIF1B	Uncertain significance	criteria provided, multiple submitters, no conflicts
1342025	NM_001365951.3(KIF1B):c.2115+6281A>G	KIF1B	Uncertain significance	criteria provided, single submitter
1342175	NM_001365951.3(KIF1B):c.4922C>T (p.Ser1641Phe)	KIF1B	Uncertain significance	criteria provided, multiple submitters, no conflicts
1379326	NM_001365951.3(KIF1B):c.3827C>T (p.Ala1276Val)	KIF1B	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 8 · 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
KIF1B	Supportive	Autosomal dominant	Charcot-Marie-Tooth disease type 2A1	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KIF1B	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
KIF1B	Orphanet:99946	Autosomal dominant Charcot-Marie-Tooth disease type 2A1
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
DGAT2	Orphanet:487814	Autosomal dominant Charcot-Marie-Tooth disease type 2 due to DGAT2 mutation

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KIF1B	HGNC:16636	ENSG00000054523	O60333	Kinesin-like protein KIF1B	gencc,clinvar
MFN2	HGNC:16877	ENSG00000116688	O95140	Mitofusin-2	clinvar
DGAT2	HGNC:16940	ENSG00000062282	Q96PD7	Diacylglycerol O-acyltransferase 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KIF1B	Kinesin-like protein KIF1B	Has a plus-end-directed microtubule motor activity and functions as a motor for transport of vesicles and organelles along microtubules.
MFN2	Mitofusin-2	Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion.
DGAT2	Diacylglycerol O-acyltransferase 2	Essential acyltransferase that catalyzes the terminal and only committed step in triacylglycerol synthesis by using diacylglycerol and fatty acyl CoA as substrates.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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	5.8×	0.345
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KIF1B	Scaffold/PPI	no		FHA_dom, Kinesin_motor_dom, PH_domain
MFN2	Other/Unknown	no		Fzo/mitofusin_HR2, Mitofusin_fam, P-loop_NTPase
DGAT2	Enzyme (other)	yes	2.3.1.20	DAGAT

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
biceps brachii	1
medial globus pallidus	1
skeletal muscle tissue of rectus abdominis	1
apex of heart	1
cardiac ventricle	1
heart left ventricle	1
right lobe of liver	1
upper arm skin	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KIF1B	287	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, biceps brachii, medial globus pallidus
MFN2	297	ubiquitous	marker	apex of heart, heart left ventricle, cardiac ventricle
DGAT2	215	ubiquitous	marker	upper arm skin, upper leg skin, right lobe of liver

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MFN2	3,853
KIF1B	2,257
DGAT2	1,613

Intra-cohort edges

A	B	Sources
KIF1B	MFN2	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MFN2	O95140	3
KIF1B	O60333	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DGAT2	Q96PD7	88.52

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 3 evidence-associated genes (3 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 3 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	761.3×	0.009	MFN2
Acyl chain remodeling of DAG and TAG	1	543.8×	0.009	DGAT2
RHOT2 GTPase cycle	1	543.8×	0.009	MFN2
Factors involved in megakaryocyte development and platelet production	2	44.3×	0.009	KIF1B, MFN2
Hemostasis	2	24.0×	0.009	KIF1B, MFN2
Mitophagy	1	346.1×	0.010	MFN2
Triglyceride biosynthesis	1	223.9×	0.013	DGAT2
PINK1-PRKN Mediated Mitophagy	1	119.0×	0.021	MFN2
Selective autophagy	1	92.8×	0.024	MFN2
Kinesins	1	59.5×	0.033	KIF1B
Autophagy	1	49.4×	0.037	MFN2
Golgi-to-ER retrograde transport	1	44.3×	0.037	KIF1B
Macroautophagy	1	38.5×	0.038	MFN2
COPI-dependent Golgi-to-ER retrograde traffic	1	37.0×	0.038	KIF1B
Intra-Golgi and retrograde Golgi-to-ER traffic	1	34.9×	0.038	KIF1B
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	27.6×	0.045	DGAT2
Membrane Trafficking	1	12.4×	0.092	KIF1B
Vesicle-mediated transport	1	11.6×	0.092	KIF1B
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	11.2×	0.092	MFN2
Signal Transduction	1	3.4×	0.267	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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of plasma lipoprotein particle levels	1	5617.3×	0.005	DGAT2
regulation of lipoprotein metabolic process	1	1872.4×	0.005	DGAT2
cellular response to oleic acid	1	1872.4×	0.005	DGAT2
type 2 mitophagy	1	1123.5×	0.005	MFN2
retrograde neuronal dense core vesicle transport	1	1123.5×	0.005	KIF1B
mitochondrial membrane organization	1	802.5×	0.005	MFN2
long-chain fatty-acyl-CoA metabolic process	1	802.5×	0.005	DGAT2
positive regulation of vascular associated smooth muscle cell apoptotic process	1	702.2×	0.005	MFN2
diacylglycerol biosynthetic process	1	624.1×	0.005	DGAT2
neuron-neuron synaptic transmission	1	561.7×	0.005	KIF1B
intracellular triglyceride homeostasis	1	561.7×	0.005	DGAT2
negative regulation of fatty acid oxidation	1	561.7×	0.005	DGAT2
mitochondrion localization	1	561.7×	0.005	MFN2
fat pad development	1	561.7×	0.005	DGAT2
apoptotic process involved in development	1	561.7×	0.005	KIF1B
monoacylglycerol biosynthetic process	1	510.7×	0.005	DGAT2
mitochondrion transport along microtubule	1	468.1×	0.005	KIF1B
positive regulation of triglyceride biosynthetic process	1	432.1×	0.005	DGAT2
diacylglycerol metabolic process	1	401.2×	0.005	DGAT2
glycerol metabolic process	1	374.5×	0.005	DGAT2
regulation of cholesterol metabolic process	1	374.5×	0.005	DGAT2
low-density lipoprotein particle clearance	1	330.4×	0.005	DGAT2
protein localization to phagophore assembly site	1	330.4×	0.005	MFN2
anterograde synaptic vesicle transport	1	330.4×	0.005	KIF1B
fatty acid homeostasis	1	312.1×	0.006	DGAT2
mitochondrial fusion	1	280.9×	0.006	MFN2
blastocyst formation	1	255.3×	0.006	MFN2
positive regulation of gluconeogenesis	1	255.3×	0.006	DGAT2
camera-type eye morphogenesis	1	255.3×	0.006	MFN2
apoptotic process	2	19.1×	0.006	KIF1B, MFN2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 3 of 3 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
DGAT2	OBETICHOLIC ACID

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DGAT2	3	4
KIF1B	0	0
MFN2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
OBETICHOLIC ACID	4	DGAT2
PF-06865571	2	DGAT2
AZD-7687	1	DGAT2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
DGAT2	61	Binding:60, ADMET:1
MFN2	3	Binding:3
KIF1B	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DGAT2	2.3.1.20	diacylglycerol O-acyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

3 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.

Compound	Max phase	Cohort target (bioactivity)
OBETICHOLIC ACID	4	DGAT2
PF-06865571	2	DGAT2
AZD-7687	1	DGAT2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	DGAT2
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	2	KIF1B, MFN2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KIF1B	1	—
MFN2	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05902351	Not specified	RECRUITING	Natural History Study for Charcot Marie Tooth Disease
NCT03550300	Not specified	UNKNOWN	Muscle MRI in Charcot Mary Tooth Disease: a Prospective Cohort Study
NCT04881201	Not specified	COMPLETED	Metabolomic Exploration of Dysregulated Lipid Metabolism in MFN2-related CMT2A (MetaDLM_CMT2A)