Charcot-Marie-Tooth disease axonal type 2S

Summary

Charcot-Marie-Tooth disease axonal type 2S (MONDO:0014511) is a disease caused by IGHMBP2 (GenCC Definitive), with 1 cohort gene and 2 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: IGHMBP2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 1,166
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		35	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease axonal type 2S
Mondo ID	MONDO:0014511
OMIM	616155
Orphanet	443073
DOID	DOID:0110171
UMLS	C4015349
MedGen	863786
GARD	0017751
Is cancer (heuristic)	no

Also known as: Charcot-Marie-Tooth disease caused by mutation in IGHMBP2 · Charcot-Marie-Tooth disease type 2S · Charcot-Marie-Tooth disease, axonal, type 2S · CMT2S · IGHMBP2 Charcot-Marie-Tooth disease

Data availability: 1,166 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 2 › Charcot-Marie-Tooth disease axonal type 2S

Related subtypes (37): Charcot-Marie-Tooth disease type 2A1, 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 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

600 retrieved; paginated sample, class counts are floors:

310 likely benign, 168 uncertain significance, 34 conflicting classifications of pathogenicity, 33 pathogenic, 17 benign, 16 pathogenic/likely pathogenic, 15 benign/likely benign, 7 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1066593	NM_002180.3(IGHMBP2):c.1730T>G (p.Leu577Arg)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070991	NM_002180.3(IGHMBP2):c.763_767del (p.Leu255fs)	IGHMBP2	Pathogenic	criteria provided, single submitter
1073962	NC_000011.9:g.(?68671411)(68707209_?)del	IGHMBP2	Pathogenic	criteria provided, single submitter
1075876	NM_002180.3(IGHMBP2):c.373C>T (p.Gln125Ter)	IGHMBP2	Pathogenic	criteria provided, single submitter
1175183	NM_002180.3(IGHMBP2):c.1061-2A>G	IGHMBP2	Pathogenic	criteria provided, multiple submitters, no conflicts
1299363	NM_002180.3(IGHMBP2):c.2796del (p.Cys932fs)	IGHMBP2	Pathogenic	criteria provided, multiple submitters, no conflicts
1371633	NM_002180.3(IGHMBP2):c.696_700del (p.Lys233fs)	IGHMBP2	Pathogenic	criteria provided, single submitter
1379465	NM_002180.3(IGHMBP2):c.1305_1350del (p.Arg436fs)	IGHMBP2	Pathogenic	criteria provided, single submitter
1393140	NM_002180.3(IGHMBP2):c.467del (p.Lys156fs)	IGHMBP2	Pathogenic	criteria provided, single submitter
1426154	NM_002180.3(IGHMBP2):c.1477A>G (p.Thr493Ala)	IGHMBP2	Pathogenic	criteria provided, single submitter
1451211	NM_002180.3(IGHMBP2):c.211C>T (p.Arg71Ter)	IGHMBP2	Pathogenic	criteria provided, single submitter
1468031	NM_002180.3(IGHMBP2):c.1126G>A (p.Glu376Lys)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
162194	NM_002180.3(IGHMBP2):c.138T>A (p.Cys46Ter)	IGHMBP2	Pathogenic	criteria provided, multiple submitters, no conflicts
162195	NM_002180.3(IGHMBP2):c.2911_2912del (p.Arg971fs)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
162197	NM_002180.3(IGHMBP2):c.1118T>G (p.Val373Gly)	IGHMBP2	Pathogenic	no assertion criteria provided
1945190	NM_002180.3(IGHMBP2):c.891del (p.Lys298fs)	IGHMBP2	Pathogenic	criteria provided, single submitter
2033010	NM_002180.3(IGHMBP2):c.317_318insA (p.Thr107fs)	IGHMBP2	Pathogenic	criteria provided, single submitter
204303	NM_002180.3(IGHMBP2):c.449+1G>T	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
204304	NM_002180.3(IGHMBP2):c.2784+1G>T	IGHMBP2	Pathogenic	criteria provided, single submitter
2130513	NM_002180.3(IGHMBP2):c.1919_1920dup (p.Glu641fs)	IGHMBP2	Pathogenic	criteria provided, single submitter
2157555	NM_002180.3(IGHMBP2):c.1969dup (p.Gln657fs)	IGHMBP2	Pathogenic	criteria provided, single submitter
217448	NM_002180.3(IGHMBP2):c.2T>C (p.Met1Thr)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217449	NM_002180.3(IGHMBP2):c.983_987del (p.Lys328fs)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217450	NM_002180.3(IGHMBP2):c.1478C>T (p.Thr493Ile)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
228355	NM_002180.3(IGHMBP2):c.127C>T (p.Arg43Ter)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
234316	NM_002180.3(IGHMBP2):c.1488C>A (p.Cys496Ter)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
235774	NM_002180.3(IGHMBP2):c.1808G>A (p.Arg603His)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2424363	NC_000011.9:g.(?68671421)(68679091_?)del	IGHMBP2	Pathogenic	criteria provided, single submitter
2424364	NC_000011.9:g.(?68673517)(68682511_?)del	IGHMBP2	Pathogenic	criteria provided, single submitter
2424365	NC_000011.9:g.(?68682271)(68682511_?)del	IGHMBP2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 2 · 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
IGHMBP2	Definitive	Autosomal recessive	Charcot-Marie-Tooth disease axonal type 2S	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IGHMBP2	Orphanet:443073	Charcot-Marie-Tooth disease type 2S
IGHMBP2	Orphanet:98920	Spinal muscular atrophy with respiratory distress type 1

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
IGHMBP2	HGNC:5542	ENSG00000132740	P38935	DNA-binding protein SMUBP-2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IGHMBP2	DNA-binding protein SMUBP-2	5’ to 3’ helicase that unwinds RNA and DNA duplexes in an ATP-dependent reaction.

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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IGHMBP2	Transcription factor	no	3.6.4.12	Znf_AN1, R3H_dom, AAA+_ATPase

Expression context

Cohort genes with no expression data: 0.

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
esophagogastric junction muscularis propria	1
lower esophagus muscularis layer	1
mucosa of stomach	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IGHMBP2	189	ubiquitous	yes	mucosa of stomach, esophagogastric junction muscularis propria, lower esophagus muscularis layer

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IGHMBP2	1,265

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IGHMBP2	P38935	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
IGHMBP2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
IGHMBP2	3.6.4.12	DNA helicase

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	IGHMBP2

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)
IGHMBP2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05152823	PHASE1/PHASE2	ENROLLING_BY_INVITATION	Gene Therapy for IGHMBP2-Related Diseases
NCT05902351	Not specified	RECRUITING	Natural History Study for Charcot Marie Tooth Disease