Charcot-Marie-Tooth disease type 4B3

Summary

Charcot-Marie-Tooth disease type 4B3 (MONDO:0014117) is a disease caused by SBF1 (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SBF1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 142
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease type 4B3
Mondo ID	MONDO:0014117
OMIM	615284
Orphanet	363981
DOID	DOID:0110194
SNOMED CT	763345008
UMLS	C3695063
MedGen	811329
GARD	0017578
Is cancer (heuristic)	no

Also known as: Charcot-Marie-Tooth disease type 4 caused by mutation in SBF1 · Charcot-Marie-Tooth disease with focally folded myelin · Charcot-Marie-Tooth disease, type 4B3 · CMT4B3 · SBF1 Charcot-Marie-Tooth disease type 4

Data availability: 142 ClinVar variants · 4 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 4B3

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 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 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

142 retrieved; paginated sample, class counts are floors:

46 uncertain significance, 26 benign/likely benign, 22 benign, 21 likely benign, 18 conflicting classifications of pathogenicity, 5 likely pathogenic, 2 pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1120017	NM_001242898.2(PPP6R2):c.228-326A>G	LOC126863186	Pathogenic	no assertion criteria provided
1120016	NM_002972.4(SBF1):c.2289C>T (p.Arg763=)	SBF1	Pathogenic	no assertion criteria provided
51005	NM_002972.4(SBF1):c.1249A>G (p.Met417Val)	SBF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
807487	NM_002972.4(SBF1):c.3826+1G>A	SBF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1030606	NM_002972.4(SBF1):c.161G>A (p.Trp54Ter)	SBF1	Likely pathogenic	criteria provided, single submitter
1065826	NM_002972.4(SBF1):c.2288G>A (p.Arg763His)	SBF1	Likely pathogenic	no assertion criteria provided
1301645	NM_002972.4(SBF1):c.5463C>G (p.Tyr1821Ter)	SBF1	Likely pathogenic	criteria provided, single submitter
1805204	NM_002972.4(SBF1):c.2948T>C (p.Leu983Pro)	SBF1	Likely pathogenic	criteria provided, single submitter
1805241	NM_002972.4(SBF1):c.2569+2T>C	SBF1	Likely pathogenic	criteria provided, single submitter
1033556	NM_002972.4(SBF1):c.2763A>G (p.Ala921=)	SBF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1120019	NM_002972.4(SBF1):c.3191G>A (p.Gly1064Glu)	SBF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1330391	NM_002972.4(SBF1):c.142-3C>T	SBF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
162096	NM_002972.4(SBF1):c.1327G>A (p.Asp443Asn)	SBF1	Conflicting classifications of pathogenicity	no assertion criteria provided
374672	NM_002972.4(SBF1):c.898-4G>A	SBF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
440252	NM_002972.4(SBF1):c.3157C>T (p.Arg1053Trp)	SBF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
444592	NM_002972.4(SBF1):c.3147-8G>C	SBF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
51006	NM_002972.4(SBF1):c.4768A>G (p.Thr1590Ala)	SBF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
522645	NM_002972.4(SBF1):c.4378T>G (p.Leu1460Val)	SBF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
618865	NM_002972.4(SBF1):c.4965G>C (p.Gln1655His)	SBF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
623999	NM_002972.4(SBF1):c.5471G>A (p.Arg1824His)	SBF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
638527	NM_002972.4(SBF1):c.1918G>C (p.Glu640Gln)	SBF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
709964	NM_002972.4(SBF1):c.2393A>G (p.Asn798Ser)	SBF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
726291	NM_002972.4(SBF1):c.3922C>T (p.Arg1308Trp)	SBF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
729706	NM_002972.4(SBF1):c.2785G>A (p.Val929Ile)	SBF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
729707	NM_002972.4(SBF1):c.2255C>T (p.Thr752Met)	SBF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
730967	NM_002972.4(SBF1):c.3940A>G (p.Ser1314Gly)	SBF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
781921	NM_002972.4(SBF1):c.4927C>A (p.Pro1643Thr)	SBF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030607	NM_002972.4(SBF1):c.1696G>T (p.Val566Leu)	SBF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1030608	NM_002972.4(SBF1):c.2938G>A (p.Gly980Arg)	SBF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1033958	NM_002972.4(SBF1):c.4834G>A (p.Val1612Met)	SBF1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
SBF1	Strong	Autosomal recessive	Charcot-Marie-Tooth disease type 4B3	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SBF1	Orphanet:363981	Charcot-Marie-Tooth disease type 4B3

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
SBF1	HGNC:10542	ENSG00000100241	O95248	Myotubularin-related protein 5	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SBF1	Myotubularin-related protein 5	Acts as an adapter for the phosphatase MTMR2 to regulate MTMR2 catalytic activity and subcellular location.

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)
SBF1	Phosphatase	yes	3.1.3.16	cDENN_dom, PH_domain, GRAM

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
left testis	1
right lobe of thyroid gland	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SBF1	278	ubiquitous	yes	left testis, right testis, right lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SBF1	1,829

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SBF1	O95248	74.72

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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	SBF1
Rab regulation of trafficking	1	368.4×	0.008	SBF1
PI Metabolism	1	356.9×	0.008	SBF1
Phospholipid metabolism	1	200.3×	0.011	SBF1
RAB GEFs exchange GTP for GDP on RABs	1	124.1×	0.015	SBF1
Membrane Trafficking	1	37.1×	0.036	SBF1
Vesicle-mediated transport	1	34.8×	0.036	SBF1
Metabolism of lipids	1	31.6×	0.036	SBF1
Metabolism	1	11.6×	0.086	SBF1

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
phosphatidylinositol biosynthetic process	1	366.4×	0.007	SBF1
protein dephosphorylation	1	221.7×	0.007	SBF1
spermatid development	1	145.3×	0.007	SBF1

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
SBF1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SBF1	3.1.3.16	protein-serine/threonine 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	0
D	Druggable family + AlphaFold only, no drug	1	SBF1
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)
SBF1	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