Charcot-Marie-Tooth disease type 4C

Summary

Charcot-Marie-Tooth disease type 4C (MONDO:0011113) is a disease caused by SH3TC2 (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: SH3TC2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 649
• Phenotypes (HPO): 51
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

51 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0001760	Abnormal foot morphology	Very frequent (80-99%)
HP:0003380	Decreased number of peripheral myelinated nerve fibers	Very frequent (80-99%)
HP:0003431	Decreased motor nerve conduction velocity	Very frequent (80-99%)
HP:0003444	EMG: chronic denervation signs	Very frequent (80-99%)
HP:0004302	Functional motor deficit	Very frequent (80-99%)
HP:0007108	Demyelinating peripheral neuropathy	Very frequent (80-99%)
HP:0007141	Sensorimotor neuropathy	Very frequent (80-99%)
HP:0001284	Areflexia	Frequent (30-79%)
HP:0001308	Tongue fasciculations	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0001765	Hammertoe	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002359	Frequent falls	Frequent (30-79%)
HP:0002460	Distal muscle weakness	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0003326	Myalgia	Frequent (30-79%)
HP:0003394	Muscle spasm	Frequent (30-79%)
HP:0003693	Distal amyotrophy	Frequent (30-79%)
HP:0006886	Impaired distal vibration sensation	Frequent (30-79%)
HP:0008443	Spinal deformities	Frequent (30-79%)
HP:0009027	Foot dorsiflexor weakness	Frequent (30-79%)
HP:0000183	Tongue muscle weakness	Occasional (5-29%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000587	Abnormal optic nerve morphology	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000651	Diplopia	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0001385	Hip dysplasia	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001604	Vocal cord paresis	Occasional (5-29%)
HP:0001763	Pes planus	Occasional (5-29%)
HP:0002093	Respiratory insufficiency	Occasional (5-29%)
HP:0002307	Drooling	Occasional (5-29%)
HP:0002346	Head tremor	Occasional (5-29%)
HP:0002403	Positive Romberg sign	Occasional (5-29%)
HP:0002540	Inability to walk	Occasional (5-29%)
HP:0002791	Hypoventilation	Occasional (5-29%)
HP:0007209	Facial paralysis	Occasional (5-29%)
HP:0007328	Impaired pain sensation	Occasional (5-29%)
HP:0007695	Abnormal pupillary light reflex	Occasional (5-29%)
HP:0009916	Anisocoria	Occasional (5-29%)
HP:0010871	Sensory ataxia	Occasional (5-29%)
HP:0012473	Tongue atrophy	Occasional (5-29%)
HP:0030319	Weakness of facial musculature	Occasional (5-29%)
HP:0000648	Optic atrophy	Very rare (<1-4%)
HP:0007994	Peripheral visual field loss	Very rare (<1-4%)
HP:0008081	Pes valgus	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease type 4C
Mondo ID	MONDO:0011113
MeSH	C535423
OMIM	601596
Orphanet	99949
DOID	DOID:0110183
ICD-11	382219984
NCIT	C129864
SNOMED CT	715797002
UMLS	C1866636
MedGen	356581
GARD	0009201
Is cancer (heuristic)	no

Also known as: Charcot Marie Tooth disease type 4C · Charcot-Marie-Tooth disease type 4 caused by mutation in SH3TC2 · Charcot-Marie-Tooth disease type 4C · Charcot-Marie-Tooth disease, type 4C · CMT 4C · CMT4C · SH3TC2 Charcot-Marie-Tooth disease type 4

Data availability: 649 ClinVar variants · 3 GenCC gene-disease records · 1 cell line.

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 4C

Related subtypes (11): Charcot-Marie-Tooth disease type 4A, Charcot-Marie-Tooth disease type 4B1, Charcot-Marie-Tooth disease type 4D, 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

600 retrieved; paginated sample, class counts are floors:

270 uncertain significance, 86 conflicting classifications of pathogenicity, 76 benign, 47 likely benign, 44 benign/likely benign, 32 pathogenic, 26 likely pathogenic, 19 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1012529	NM_024577.4(SH3TC2):c.819dup (p.Lys274Ter)	SH3TC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1030852	NM_024577.4(SH3TC2):c.383T>G (p.Leu128Ter)	SH3TC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1120206	NM_024577.4(SH3TC2):c.233_239del (p.Leu78fs)	SH3TC2	Pathogenic	no assertion criteria provided
1172758	NM_024577.4(SH3TC2):c.2599C>T (p.Gln867Ter)	SH3TC2	Pathogenic	criteria provided, single submitter
1444894	NM_024577.4(SH3TC2):c.3627T>A (p.Tyr1209Ter)	SH3TC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1457295	NM_024577.4(SH3TC2):c.620C>G (p.Ser207Ter)	SH3TC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1686184	NM_024577.4(SH3TC2):c.731+2T>G	SH3TC2	Pathogenic	criteria provided, single submitter
1687474	NM_024577.4(SH3TC2):c.929dup (p.Ser312fs)	SH3TC2	Pathogenic	criteria provided, multiple submitters, no conflicts
216005	NM_024577.4(SH3TC2):c.1586_1587delinsAG (p.Arg529Gln)	SH3TC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21688	NM_024577.4(SH3TC2):c.1178-1G>A	SH3TC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21689	NM_024577.4(SH3TC2):c.1969G>A (p.Glu657Lys)	SH3TC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21690	NM_024577.4(SH3TC2):c.1972C>T (p.Arg658Cys)	SH3TC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21694	NM_024577.4(SH3TC2):c.2491_2492del (p.Leu832fs)	SH3TC2	Pathogenic	criteria provided, multiple submitters, no conflicts
21696	NM_024577.4(SH3TC2):c.2710C>T (p.Arg904Ter)	SH3TC2	Pathogenic	criteria provided, multiple submitters, no conflicts
21699	NM_024577.4(SH3TC2):c.3341del (p.Pro1114fs)	SH3TC2	Pathogenic	criteria provided, single submitter
21700	NM_024577.4(SH3TC2):c.3601C>T (p.Gln1201Ter)	SH3TC2	Pathogenic	criteria provided, single submitter
218918	NM_024577.4(SH3TC2):c.1A>G (p.Met1Val)	SH3TC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
220408	NM_024577.4(SH3TC2):c.3154C>T (p.Arg1052Ter)	SH3TC2	Pathogenic	criteria provided, multiple submitters, no conflicts
220821	NM_024577.4(SH3TC2):c.211C>T (p.Gln71Ter)	SH3TC2	Pathogenic	criteria provided, multiple submitters, no conflicts
220822	NM_024577.4(SH3TC2):c.3303del (p.Arg1101fs)	SH3TC2	Pathogenic	criteria provided, multiple submitters, no conflicts
241502	NM_024577.4(SH3TC2):c.2072_2090del (p.Ala691fs)	SH3TC2	Pathogenic	criteria provided, single submitter
243068	NM_024577.4(SH3TC2):c.820_821insT (p.Lys274fs)	SH3TC2	Pathogenic	criteria provided, single submitter
2431041	NM_024577.4(SH3TC2):c.1267G>T (p.Glu423Ter)	SH3TC2	Pathogenic	no assertion criteria provided
246578	NM_024577.4(SH3TC2):c.2488G>T (p.Glu830Ter)	SH3TC2	Pathogenic	criteria provided, multiple submitters, no conflicts
2479	NM_024577.4(SH3TC2):c.1747_1748del (p.Arg583fs)	SH3TC2	Pathogenic	criteria provided, single submitter
2481	NM_024577.4(SH3TC2):c.2829T>G (p.Tyr943Ter)	SH3TC2	Pathogenic	criteria provided, multiple submitters, no conflicts
2482	NM_024577.4(SH3TC2):c.2860C>T (p.Arg954Ter)	SH3TC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2483	NM_024577.4(SH3TC2):c.3325C>T (p.Arg1109Ter)	SH3TC2	Pathogenic	criteria provided, multiple submitters, no conflicts
2501663	NM_024577.4(SH3TC2):c.1691A>G (p.Asp564Gly)	SH3TC2	Pathogenic/Likely pathogenic	no assertion criteria provided
3591876	NM_024577.4(SH3TC2):c.2305G>T (p.Glu769Ter)	SH3TC2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
SH3TC2	Definitive	Autosomal recessive	Charcot-Marie-Tooth disease type 4C	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SH3TC2	Orphanet:99949	Charcot-Marie-Tooth disease type 4C

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
SH3TC2	HGNC:29427	ENSG00000169247	Q8TF17	SH3 domain and tetratricopeptide repeat-containing protein 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SH3TC2	SH3 domain and tetratricopeptide repeat-containing protein 2	Is involved in nerve myelination and is required for the integrity of nodes of Ranvier.

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
Scaffold/PPI	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SH3TC2	Scaffold/PPI	no		SH3_domain, TPR-like_helical_dom_sf, TPR_rpt

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
C1 segment of cervical spinal cord	1
corpus callosum	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SH3TC2	168	broad	marker	corpus callosum, sural nerve, C1 segment of cervical spinal cord

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SH3TC2	569

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SH3TC2	Q8TF17	78.63

Function

Pathway analysis

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

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
regulation of ERBB signaling pathway	1	16852.0×	2e-04	SH3TC2
regulation of intracellular protein transport	1	2808.7×	7e-04	SH3TC2
regulation of endocytic recycling	1	1685.2×	7e-04	SH3TC2
peripheral nervous system myelin maintenance	1	1532.0×	7e-04	SH3TC2

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
SH3TC2	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	SH3TC2

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)
SH3TC2	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