Charcot-Marie-Tooth disease recessive intermediate C

Summary

Charcot-Marie-Tooth disease recessive intermediate C (MONDO:0014154) is a disease caused by PLEKHG5 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: (Worldwide) [Orphanet-validated]
• Causal gene: PLEKHG5 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 1,223

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		Europe	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease recessive intermediate C
Mondo ID	MONDO:0014154
OMIM	615376
Orphanet	369867
DOID	DOID:0110198
UMLS	C3809309
MedGen	815639
GARD	0017587
Is cancer (heuristic)	no

Also known as: autosomal recessive intermediate Charcot-Marie-Tooth disease type C · Charcot-Marie-Tooth disease caused by mutation in PLEKHG5 · Charcot-Marie-Tooth disease recessive intermediate type C · Charcot-Marie-Tooth disease, recessive intermediate C · Charcot-Marie-Tooth disease, recessive Intermediate type C · CMTRIC · PLEKHG5 Charcot-Marie-Tooth disease · RI-CMT type C · RI-CMTC

Data availability: 1,223 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive intermediate Charcot-Marie-Tooth disease › Charcot-Marie-Tooth disease recessive intermediate C

Related subtypes (3): Charcot-Marie-Tooth disease recessive intermediate A, Charcot-Marie-Tooth disease recessive intermediate B, Charcot-Marie-Tooth disease recessive intermediate D

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:

318 likely benign, 212 uncertain significance, 22 conflicting classifications of pathogenicity, 19 benign, 14 pathogenic, 6 pathogenic/likely pathogenic, 6 benign/likely benign, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069212	NM_020631.6(PLEKHG5):c.909C>A (p.Tyr303Ter)	PLEKHG5	Pathogenic	criteria provided, single submitter
1073676	NM_020631.6(PLEKHG5):c.2149G>T (p.Glu717Ter)	PLEKHG5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1146824	NM_020631.6(PLEKHG5):c.2162_2163insTGAGCAGGAGGAGGAAGAGGAGGAGGAGGAGGAG (p.Glu721fs)	PLEKHG5	Pathogenic	criteria provided, single submitter
1163123	NM_020631.6(PLEKHG5):c.1738G>T (p.Glu580Ter)	PLEKHG5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1333504	NM_020631.6(PLEKHG5):c.1132-2A>C	PLEKHG5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1416561	NM_020631.6(PLEKHG5):c.386del (p.Leu129fs)	PLEKHG5	Pathogenic	criteria provided, single submitter
1424950	NM_020631.6(PLEKHG5):c.1457_1482del (p.Gln486fs)	PLEKHG5	Pathogenic	criteria provided, single submitter
1453868	NM_020631.6(PLEKHG5):c.2074_2075del (p.Gln692fs)	PLEKHG5	Pathogenic	criteria provided, single submitter
1454196	NM_020631.6(PLEKHG5):c.1289C>A (p.Ser430Ter)	PLEKHG5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1788740	NM_020631.6(PLEKHG5):c.2269G>T (p.Glu757Ter)	PLEKHG5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1796001	NM_020631.6(PLEKHG5):c.2788C>T (p.Arg930Ter)	PLEKHG5	Pathogenic	criteria provided, multiple submitters, no conflicts
1909611	NM_020631.6(PLEKHG5):c.2902del (p.Val968fs)	PLEKHG5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1999132	NM_020631.6(PLEKHG5):c.1128T>A (p.Cys376Ter)	PLEKHG5	Pathogenic	criteria provided, single submitter
2033307	NM_020631.6(PLEKHG5):c.363C>A (p.Tyr121Ter)	PLEKHG5	Pathogenic	criteria provided, single submitter
2035800	NM_020631.6(PLEKHG5):c.365_378del (p.Leu122fs)	PLEKHG5	Pathogenic	criteria provided, single submitter
2065924	NM_020631.6(PLEKHG5):c.2540del (p.Pro847fs)	PLEKHG5	Pathogenic	criteria provided, single submitter
2135331	NM_020631.6(PLEKHG5):c.1258del (p.Asp420fs)	PLEKHG5	Pathogenic	criteria provided, single submitter
2921807	NM_020631.6(PLEKHG5):c.2665del (p.Ala889fs)	PLEKHG5	Pathogenic	criteria provided, single submitter
2925088	NM_020631.6(PLEKHG5):c.2158G>T (p.Glu720Ter)	PLEKHG5	Pathogenic	criteria provided, single submitter
2932016	NM_020631.6(PLEKHG5):c.2945del (p.Lys982fs)	PLEKHG5	Pathogenic	criteria provided, single submitter
1490708	NM_020631.6(PLEKHG5):c.1132-1G>T	PLEKHG5	Likely pathogenic	criteria provided, single submitter
1691304	NM_001042663.3(PLEKHG5):c.22_23insGGCC (p.Lys8fs)	PLEKHG5	Likely pathogenic	criteria provided, single submitter
1967038	NM_020631.6(PLEKHG5):c.1934-2A>C	PLEKHG5	Likely pathogenic	criteria provided, single submitter
1028662	NM_020631.6(PLEKHG5):c.1393-16C>G	PLEKHG5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1080853	NM_020631.6(PLEKHG5):c.1393-5C>T	PLEKHG5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1160373	NM_020631.6(PLEKHG5):c.1543-5C>T	PLEKHG5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1308498	NM_020631.6(PLEKHG5):c.1393-10C>A	PLEKHG5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1398214	NM_020631.6(PLEKHG5):c.1874G>A (p.Arg625Lys)	PLEKHG5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1403245	NM_020631.6(PLEKHG5):c.784G>A (p.Ala262Thr)	PLEKHG5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1559995	NM_020631.6(PLEKHG5):c.796-4C>T	PLEKHG5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
PLEKHG5	Strong	Autosomal recessive	Charcot-Marie-Tooth disease recessive intermediate C	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PLEKHG5	Orphanet:206580	Autosomal recessive lower motor neuron disease with childhood onset
PLEKHG5	Orphanet:369867	Autosomal recessive intermediate Charcot-Marie-Tooth disease type C

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
PLEKHG5	HGNC:29105	ENSG00000171680	O94827	Pleckstrin homology domain-containing family G member 5	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PLEKHG5	Pleckstrin homology domain-containing family G member 5	Functions as a guanine exchange factor (GEF) for RAB26 and thus regulates autophagy of synaptic vesicles in axon terminal of motoneurons.

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)
PLEKHG5	Scaffold/PPI	no		DH_dom, PH_domain, PH-like_dom_sf

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
cerebellar hemisphere	1
right hemisphere of cerebellum	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PLEKHG5	175	ubiquitous	yes	sural nerve, right hemisphere of cerebellum, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PLEKHG5	966

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PLEKHG5	O94827	64.94

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
RND1 GTPase cycle	1	265.6×	0.009	PLEKHG5
RND3 GTPase cycle	1	259.6×	0.009	PLEKHG5
NRAGE signals death through JNK	1	184.2×	0.009	PLEKHG5
G alpha (12/13) signalling events	1	137.6×	0.009	PLEKHG5
RHOA GTPase cycle	1	74.6×	0.013	PLEKHG5

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
endothelial cell chemotaxis	1	1685.2×	0.003	PLEKHG5
endothelial cell migration	1	411.0×	0.006	PLEKHG5
Rho protein signal transduction	1	247.8×	0.007	PLEKHG5
regulation of small GTPase mediated signal transduction	1	144.0×	0.009	PLEKHG5
positive regulation of canonical NF-kappaB signal transduction	1	72.6×	0.014	PLEKHG5

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
PLEKHG5	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	PLEKHG5

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)
PLEKHG5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.