Charcot-Marie-Tooth disease type 4B1

Summary

Charcot-Marie-Tooth disease type 4B1 (MONDO:0011066) is a disease caused by MTMR2 (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MTMR2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 121
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		11	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease type 4B1
Mondo ID	MONDO:0011066
MeSH	C535420
OMIM	601382
Orphanet	99955
DOID	DOID:0110191
ICD-11	776238355
SNOMED CT	715803003
UMLS	C1832399
MedGen	321947
GARD	0001253
Is cancer (heuristic)	no

Also known as: Charcot Marie Tooth disease type 4B1 · Charcot-Marie-Tooth disease type 4 caused by mutation in MTMR2 · Charcot-Marie-Tooth disease type 4B1 · Charcot-Marie-Tooth disease, type 4B1 · CMT 4B · CMT 4B1 · CMT4B1 · MTMR2 Charcot-Marie-Tooth disease type 4

Data availability: 121 ClinVar variants · 4 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 4 › Charcot-Marie-Tooth disease type 4B1

Related subtypes (11): Charcot-Marie-Tooth disease type 4A, Charcot-Marie-Tooth disease type 4D, Charcot-Marie-Tooth disease type 4C, Charcot-Marie-Tooth disease type 4B2, Charcot-Marie-Tooth disease type 4E, Charcot-Marie-Tooth disease type 4G, Charcot-Marie-Tooth disease type 4H, Charcot-Marie-Tooth disease type 4J, Charcot-Marie-Tooth disease type 4F, Charcot-Marie-Tooth disease type 4B3, Charcot-Marie-Tooth disease type 4K

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

121 retrieved; paginated sample, class counts are floors:

44 uncertain significance, 17 benign, 16 pathogenic, 16 likely pathogenic, 12 conflicting classifications of pathogenicity, 7 benign/likely benign, 7 likely benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1803781	NM_016156.6(MTMR2):c.304C>T (p.Arg102Ter)	MTMR2	Pathogenic	criteria provided, single submitter
2190463	NM_016156.6(MTMR2):c.484C>T (p.Arg162Ter)	MTMR2	Pathogenic	criteria provided, multiple submitters, no conflicts
2637502	NM_016156.6(MTMR2):c.1096del (p.Lys367fs)	MTMR2	Pathogenic	criteria provided, single submitter
3625829	NM_016156.6(MTMR2):c.1720G>T (p.Glu574Ter)	MTMR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
406679	NM_016156.6(MTMR2):c.1537_1538dup (p.Ser514fs)	MTMR2	Pathogenic	criteria provided, multiple submitters, no conflicts
543342	NM_016156.6(MTMR2):c.464_465del (p.Val154_Cys155insTer)	MTMR2	Pathogenic	criteria provided, multiple submitters, no conflicts
549685	NM_016156.6(MTMR2):c.1164G>A (p.Trp388Ter)	MTMR2	Pathogenic	no assertion criteria provided
6231	NM_016156.6(MTMR2):c.1276C>T (p.Gln426Ter)	MTMR2	Pathogenic	criteria provided, single submitter
6233	NM_016156.6(MTMR2):c.826G>T (p.Glu276Ter)	MTMR2	Pathogenic	criteria provided, single submitter
623390	NM_016156.6(MTMR2):c.1768C>T (p.Gln590Ter)	MTMR2	Pathogenic	criteria provided, multiple submitters, no conflicts
6234	NM_016156.6(MTMR2):c.1444C>T (p.Gln482Ter)	MTMR2	Pathogenic	no assertion criteria provided
637472	NM_016156.6(MTMR2):c.1593+1G>A	MTMR2	Pathogenic	criteria provided, single submitter
684408	NM_016156.6(MTMR2):c.1490dup (p.Phe498fs)	MTMR2	Pathogenic	criteria provided, single submitter
684409	NM_016156.6(MTMR2):c.1479+1G>A	MTMR2	Pathogenic	criteria provided, single submitter
684410	NM_016156.6(MTMR2):c.1090C>T (p.Arg364Ter)	MTMR2	Pathogenic	criteria provided, multiple submitters, no conflicts
684411	NM_016156.6(MTMR2):c.883C>T (p.Arg295Ter)	MTMR2	Pathogenic	criteria provided, single submitter
804461	NM_016156.6(MTMR2):c.766_767del (p.Lys256fs)	MTMR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
993001	NM_016156.6(MTMR2):c.1736_1745delinsCC (p.Tyr579fs)	MTMR2	Pathogenic	no assertion criteria provided
2584950	NM_016156.6(MTMR2):c.771_772del (p.Arg257fs)	MTMR2	Likely pathogenic	criteria provided, single submitter
2687883	NM_016156.6(MTMR2):c.323C>T (p.Thr108Met)	MTMR2	Likely pathogenic	criteria provided, single submitter
3256761	NM_016156.6(MTMR2):c.262+5G>T	MTMR2	Likely pathogenic	no assertion criteria provided
3574137	NM_016156.6(MTMR2):c.1862_1865dup (p.Thr623fs)	MTMR2	Likely pathogenic	criteria provided, single submitter
3574138	NM_016156.6(MTMR2):c.1526del (p.Leu509fs)	MTMR2	Likely pathogenic	criteria provided, single submitter
3574139	NM_016156.6(MTMR2):c.1327C>T (p.Arg443Ter)	MTMR2	Likely pathogenic	criteria provided, single submitter
3574140	NM_016156.6(MTMR2):c.1232delinsGTCTT (p.Thr411fs)	MTMR2	Likely pathogenic	criteria provided, single submitter
3574141	NM_016156.6(MTMR2):c.447_455del (p.Tyr149_Glu152delinsTer)	MTMR2	Likely pathogenic	criteria provided, single submitter
3574142	NM_016156.6(MTMR2):c.357+1G>A	MTMR2	Likely pathogenic	criteria provided, single submitter
3574143	NM_016156.6(MTMR2):c.187-2A>G	MTMR2	Likely pathogenic	criteria provided, single submitter
3891749	NM_016156.6(MTMR2):c.358-2_358-1insCTGGCGCTGTACGAGGAACTCTGACTGTCACGAATTATAGGTTATATTTCAAAAGCATGGAACG	MTMR2	Likely pathogenic	criteria provided, single submitter
3896920	NM_016156.6(MTMR2):c.1085C>A (p.Ser362Ter)	MTMR2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
MTMR2	Strong	Autosomal recessive	Charcot-Marie-Tooth disease type 4B1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MTMR2	Orphanet:99955	Charcot-Marie-Tooth disease type 4B1

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
MTMR2	HGNC:7450	ENSG00000087053	Q13614	Phosphatidylinositol-3,5-bisphosphate 3-phosphatase MTMR2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MTMR2	Phosphatidylinositol-3,5-bisphosphate 3-phosphatase MTMR2	Lipid phosphatase that specifically dephosphorylates the D-3 position of phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate, generating phosphatidylinositol and phosphatidylinositol 5-phosphate.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Phosphatase	1	83.9×	0.012

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MTMR2	Phosphatase	yes	3.1.3.64	Tyr_Pase_dom, Tyr_Pase_cat, GRAM

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
male germ cell	1
parotid gland	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MTMR2	288	ubiquitous	marker	sperm, parotid gland, male germ cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MTMR2	1,121

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MTMR2	Q13614	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
Synthesis of PIPs at the ER membrane	1	2284.0×	0.004	MTMR2
Synthesis of PIPs at the late endosome membrane	1	951.7×	0.004	MTMR2
Synthesis of PIPs at the early endosome membrane	1	713.8×	0.004	MTMR2
PI Metabolism	1	356.9×	0.006	MTMR2
Synthesis of PIPs at the plasma membrane	1	211.5×	0.007	MTMR2
Phospholipid metabolism	1	200.3×	0.007	MTMR2
Metabolism of lipids	1	31.6×	0.036	MTMR2
Metabolism	1	11.6×	0.086	MTMR2

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
negative regulation of receptor catabolic process	1	16852.0×	7e-04	MTMR2
regulation of phosphatidylinositol dephosphorylation	1	2808.7×	0.001	MTMR2
negative regulation of myelination	1	1872.4×	0.001	MTMR2
myelin assembly	1	1872.4×	0.001	MTMR2
positive regulation of early endosome to late endosome transport	1	1872.4×	0.001	MTMR2
negative regulation of excitatory postsynaptic potential	1	1296.3×	0.001	MTMR2
dendritic spine maintenance	1	1296.3×	0.001	MTMR2
negative regulation of receptor internalization	1	1203.7×	0.001	MTMR2
negative regulation of endocytosis	1	936.2×	0.001	MTMR2
phosphatidylinositol dephosphorylation	1	648.1×	0.002	MTMR2
phosphatidylinositol biosynthetic process	1	366.4×	0.003	MTMR2
neuron development	1	255.3×	0.004	MTMR2

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
MTMR2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MTMR2	3.1.3.64, 3.1.3.95	phosphatidylinositol-3-phosphatase, phosphatidylinositol-3,5-bisphosphate 3-phosphatase

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	1	MTMR2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
MTMR2	0	—

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