Charcot-Marie-Tooth disease type 2B

Summary

Charcot-Marie-Tooth disease type 2B (MONDO:0010949) is a disease caused by RAB7A (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RAB7A (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 170

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 2B
Mondo ID	MONDO:0010949
MeSH	C537989
OMIM	600882
Orphanet	99936
DOID	DOID:0110159
ICD-11	1425224652
SNOMED CT	717008005
UMLS	C1833219
MedGen	371512
GARD	0009192
Is cancer (heuristic)	no

Also known as: autosomal dominant Charcot-Marie-Tooth disease type 2B · Charcot Marie Tooth disease type 2B · Charcot-Marie-Tooth disease type 2 caused by mutation in RAB7A · Charcot-Marie-Tooth disease, axonal, type 2B · Charcot-Marie-Tooth disease, neuronal, type 2B · Charcot-Marie-Tooth disease, type 2B · CMT 2B · CMT2B · hereditary motor and sensory neuropathy 2 B (HMSN 2 B) · HMSN2B · peripheral sensory neuropathy, autosomal dominant (PSN) · RAB7A Charcot-Marie-Tooth disease type 2

Data availability: 170 ClinVar variants · 3 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 2B

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

170 retrieved; paginated sample, class counts are floors:

73 uncertain significance, 63 likely benign, 14 benign, 10 conflicting classifications of pathogenicity, 6 benign/likely benign, 4 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
637404	NM_004637.6(RAB7A):c.482A>T (p.Asn161Ile)	RAB7A	Pathogenic	criteria provided, single submitter
7345	NM_004637.6(RAB7A):c.385C>T (p.Leu129Phe)	RAB7A	Pathogenic	criteria provided, multiple submitters, no conflicts
7346	NM_004637.6(RAB7A):c.484G>A (p.Val162Met)	RAB7A	Pathogenic	criteria provided, multiple submitters, no conflicts
846631	NM_004637.6(RAB7A):c.471G>T (p.Lys157Asn)	RAB7A	Pathogenic	criteria provided, single submitter
2389107	NM_004637.6(RAB7A):c.592G>A (p.Ala198Thr)	LOC112872299	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
532741	NM_004637.6(RAB7A):c.551A>G (p.Asn184Ser)	LOC112872299	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
574067	NM_004637.6(RAB7A):c.568A>G (p.Ile190Val)	LOC112872299	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1041821	NM_004637.6(RAB7A):c.481A>G (p.Asn161Asp)	RAB7A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1046646	NM_004637.6(RAB7A):c.503C>T (p.Thr168Met)	RAB7A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
343156	NM_004637.6(RAB7A):c.-18A>G	RAB7A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
343166	NM_004637.6(RAB7A):c.*183A>G	RAB7A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
7347	NM_004637.6(RAB7A):c.482A>C (p.Asn161Thr)	RAB7A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
7348	NM_004637.6(RAB7A):c.471G>C (p.Lys157Asn)	RAB7A	Conflicting classifications of pathogenicity	no assertion criteria provided
805267	NM_004637.6(RAB7A):c.466G>A (p.Ala156Thr)	RAB7A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1015296	NM_004637.6(RAB7A):c.533C>T (p.Thr178Met)	LOC112872299	Uncertain significance	criteria provided, multiple submitters, no conflicts
1370790	NM_004637.6(RAB7A):c.602C>T (p.Ser201Leu)	LOC112872299	Uncertain significance	criteria provided, single submitter
1381919	NM_004637.6(RAB7A):c.605C>G (p.Ala202Gly)	LOC112872299	Uncertain significance	criteria provided, single submitter
1471329	NM_004637.6(RAB7A):c.592G>T (p.Ala198Ser)	LOC112872299	Uncertain significance	criteria provided, single submitter
1502827	NM_004637.6(RAB7A):c.572A>G (p.Lys191Arg)	LOC112872299	Uncertain significance	criteria provided, single submitter
1983634	NM_004637.6(RAB7A):c.544C>A (p.Leu182Met)	LOC112872299	Uncertain significance	criteria provided, multiple submitters, no conflicts
3012538	NM_004637.6(RAB7A):c.570C>G (p.Ile190Met)	LOC112872299	Uncertain significance	criteria provided, single submitter
3661960	NM_004637.6(RAB7A):c.612C>G (p.Ser204Arg)	LOC112872299	Uncertain significance	criteria provided, single submitter
464095	NM_004637.6(RAB7A):c.577G>A (p.Asp193Asn)	LOC112872299	Uncertain significance	criteria provided, single submitter
841119	NM_004637.6(RAB7A):c.590G>A (p.Arg197Gln)	LOC112872299	Uncertain significance	criteria provided, multiple submitters, no conflicts
939028	NM_004637.6(RAB7A):c.589C>T (p.Arg197Trp)	LOC112872299	Uncertain significance	criteria provided, multiple submitters, no conflicts
1039960	NM_004637.6(RAB7A):c.403G>A (p.Ala135Thr)	RAB7A	Uncertain significance	criteria provided, single submitter
1057779	NM_004637.6(RAB7A):c.467C>G (p.Ala156Gly)	RAB7A	Uncertain significance	criteria provided, single submitter
1373051	NM_004637.6(RAB7A):c.508G>A (p.Ala170Thr)	RAB7A	Uncertain significance	criteria provided, single submitter
1447624	NM_004637.6(RAB7A):c.180+4A>T	RAB7A	Uncertain significance	criteria provided, single submitter
1474822	NM_004637.6(RAB7A):c.152T>C (p.Met51Thr)	RAB7A	Uncertain significance	criteria provided, single submitter

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
RAB7A	Definitive	Autosomal dominant	Charcot-Marie-Tooth disease type 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RAB7A	Orphanet:99936	Autosomal dominant Charcot-Marie-Tooth disease type 2B

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
RAB7A	HGNC:9788	ENSG00000075785	P51149	Ras-related protein Rab-7a	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RAB7A	Ras-related protein Rab-7a	The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RAB7A	Other/Unknown	no		Small_GTPase, Small_GTP-bd, P-loop_NTPase

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
right lung	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RAB7A	297	ubiquitous	marker	stromal cell of endometrium, right lung, C1 segment of cervical spinal cord

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RAB7A	4,226

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RAB7A	P51149	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. 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
Suppression of autophagy	1	5710.0×	0.003	RAB7A
Prevention of phagosomal-lysosomal fusion	1	1268.9×	0.007	RAB7A
RHOH GTPase cycle	1	308.6×	0.011	RAB7A
TBC/RABGAPs	1	259.6×	0.011	RAB7A
RHOF GTPase cycle	1	259.6×	0.011	RAB7A
RHOD GTPase cycle	1	203.9×	0.011	RAB7A
RHOJ GTPase cycle	1	200.3×	0.011	RAB7A
RHOQ GTPase cycle	1	181.3×	0.011	RAB7A
RAB geranylgeranylation	1	173.0×	0.011	RAB7A
RHOG GTPase cycle	1	148.3×	0.011	RAB7A
RAC2 GTPase cycle	1	126.9×	0.011	RAB7A
RAB GEFs exchange GTP for GDP on RABs	1	124.1×	0.011	RAB7A
RAC3 GTPase cycle	1	119.0×	0.011	RAB7A
MHC class II antigen presentation	1	89.2×	0.014	RAB7A
CDC42 GTPase cycle	1	72.3×	0.016	RAB7A
RAC1 GTPase cycle	1	61.1×	0.017	RAB7A
Neutrophil degranulation	1	23.1×	0.043	RAB7A

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
synaptic vesicle recycling via endosome	1	16852.0×	8e-04	RAB7A
epidermal growth factor catabolic process	1	8426.0×	8e-04	RAB7A
neurotransmitter receptor transport, postsynaptic endosome to lysosome	1	8426.0×	8e-04	RAB7A
negative regulation of intralumenal vesicle formation	1	8426.0×	8e-04	RAB7A
positive regulation of viral process	1	5617.3×	8e-04	RAB7A
lipophagy	1	5617.3×	8e-04	RAB7A
negative regulation of exosomal secretion	1	4213.0×	9e-04	RAB7A
protein to membrane docking	1	3370.4×	9e-04	RAB7A
endosome to plasma membrane protein transport	1	3370.4×	9e-04	RAB7A
establishment of vesicle localization	1	2407.4×	0.001	RAB7A
phagosome acidification	1	2407.4×	0.001	RAB7A
phagosome-lysosome fusion	1	1296.3×	0.002	RAB7A
phagosome maturation	1	1203.7×	0.002	RAB7A
positive regulation of exosomal secretion	1	1123.5×	0.002	RAB7A
protein localization to lysosome	1	1053.2×	0.002	RAB7A
viral release from host cell	1	936.2×	0.002	RAB7A
early endosome to late endosome transport	1	648.1×	0.002	RAB7A
protein targeting to lysosome	1	624.1×	0.002	RAB7A
bone resorption	1	581.1×	0.002	RAB7A
endosome to lysosome transport	1	337.0×	0.004	RAB7A
lipid catabolic process	1	244.2×	0.005	RAB7A
autophagosome assembly	1	224.7×	0.005	RAB7A
retrograde transport, endosome to Golgi	1	205.5×	0.006	RAB7A
positive regulation of protein catabolic process	1	203.0×	0.006	RAB7A
response to bacterium	1	193.7×	0.006	RAB7A
endocytosis	1	95.2×	0.011	RAB7A
protein transport	1	43.9×	0.023	RAB7A

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RAB7A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
RAB7A	33	Binding:33

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	RAB7A

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)
RAB7A	33	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.