Charcot-Marie-Tooth disease recessive intermediate A

Summary

Charcot-Marie-Tooth disease recessive intermediate A (MONDO:0012014) is a disease caused by GDAP1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GDAP1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 122

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease recessive intermediate A
Mondo ID	MONDO:0012014
MeSH	C564256
OMIM	608340
Orphanet	217055
DOID	DOID:0110201
UMLS	C1842197
MedGen	334012
GARD	0012453
Is cancer (heuristic)	no

Also known as: autosomal recessive intermediate Charcot-Marie-Tooth disease type A · Charcot-Marie-Tooth disease caused by mutation in GDAP1 · Charcot-Marie-Tooth disease recessive intermediate type A · Charcot-Marie-Tooth disease, recessive intermediate A · Charcot-Marie-Tooth disease, recessive Intermediate type a · Charcot-Marie-Tooth disease, recessive intermediate, A · CMTRIA · GDAP1 Charcot-Marie-Tooth disease · RI-CMT type A · RI-CMTA

Data availability: 122 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

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 A

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

Subtypes (2): Charcot-Marie-Tooth disease type 4A, Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive

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

122 retrieved; paginated sample, class counts are floors:

60 uncertain significance, 16 benign, 13 pathogenic/likely pathogenic, 11 pathogenic, 10 conflicting classifications of pathogenicity, 7 likely benign, 4 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
424778	NM_018972.2(GDAP1):c.[347T>C];[62delA]		Pathogenic	criteria provided, single submitter
2000577	NM_018972.4(GDAP1):c.1del (p.Met1fs)	GDAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217229	NM_018972.4(GDAP1):c.373C>T (p.Arg125Ter)	GDAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
220379	NM_018972.4(GDAP1):c.579+1G>A	GDAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
2423924	NM_018972.4(GDAP1):c.1A>G (p.Met1Val)	GDAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
245608	NM_018972.4(GDAP1):c.769C>T (p.Arg257Ter)	GDAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280104	NM_018972.4(GDAP1):c.501del (p.Glu168fs)	GDAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3595879	NM_018972.4(GDAP1):c.400del (p.Asp134fs)	GDAP1	Pathogenic	criteria provided, single submitter
38411	NM_018972.4(GDAP1):c.347T>G (p.Met116Arg)	GDAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40049	NM_018972.4(GDAP1):c.980G>A (p.Gly327Asp)	GDAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
406135	NM_018972.4(GDAP1):c.458C>T (p.Pro153Leu)	GDAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
406136	NM_018972.4(GDAP1):c.786del (p.Phe263fs)	GDAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4191	NM_018972.4(GDAP1):c.581C>G (p.Ser194Ter)	GDAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
4193	NM_018972.4(GDAP1):c.487C>T (p.Gln163Ter)	GDAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
4195	NM_018972.4(GDAP1):c.844C>T (p.Arg282Cys)	GDAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
4198	NM_018972.4(GDAP1):c.358C>T (p.Arg120Trp)	GDAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
4200	NM_018972.4(GDAP1):c.715C>T (p.Leu239Phe)	GDAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4202	NM_018972.4(GDAP1):c.692C>T (p.Pro231Leu)	GDAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
549689	NM_018972.2(GDAP1):c.695_1077del	GDAP1	Pathogenic	no assertion criteria provided
569560	NM_018972.4(GDAP1):c.112C>T (p.Gln38Ter)	GDAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
574458	NM_018972.4(GDAP1):c.694+1G>A	GDAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
618662	NM_018972.4(GDAP1):c.767A>G (p.His256Arg)	GDAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
637122	NM_018972.4(GDAP1):c.349dup (p.Tyr117fs)	GDAP1	Pathogenic	criteria provided, single submitter
637452	NM_018972.4(GDAP1):c.311-1G>A	GDAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2444286	NM_018972.4(GDAP1):c.760dup (p.Thr254fs)	GDAP1	Likely pathogenic	criteria provided, single submitter
3595880	NM_018972.4(GDAP1):c.966dup (p.Thr323fs)	GDAP1	Likely pathogenic	criteria provided, single submitter
3595876	NM_018972.4(GDAP1):c.15_16delinsAT (p.Glu6Ter)	LOC130000622	Likely pathogenic	criteria provided, single submitter
3595877	NM_018972.4(GDAP1):c.77T>G (p.Leu26Arg)	LOC130000622	Likely pathogenic	criteria provided, single submitter
1497027	NM_018972.4(GDAP1):c.191A>G (p.Asn64Ser)	GDAP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
216707	NM_018972.4(GDAP1):c.556A>G (p.Ile186Val)	GDAP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 5 · 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
GDAP1	Strong	Autosomal dominant	Charcot-Marie-Tooth disease axonal type 2K	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GDAP1	Orphanet:101097	Autosomal recessive Charcot-Marie-Tooth disease with hoarseness
GDAP1	Orphanet:101102	Charcot-Marie-Tooth disease type 2H
GDAP1	Orphanet:217055	Autosomal recessive intermediate Charcot-Marie-Tooth disease type A
GDAP1	Orphanet:99944	Autosomal dominant Charcot-Marie-Tooth disease type 2K
GDAP1	Orphanet:99948	Charcot-Marie-Tooth disease type 4A

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
GDAP1	HGNC:15968	ENSG00000104381	Q8TB36	Ganglioside-induced differentiation-associated protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GDAP1	Ganglioside-induced differentiation-associated protein 1	Regulates the mitochondrial network by promoting mitochondrial fission.

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)
GDAP1	Other/Unknown	no		Glutathione_S-Trfase_N, Glutathione-S-Trfase_C-like, GST_C_GDAP1

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
endothelial cell	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GDAP1	244	ubiquitous	yes	endothelial cell, secondary oocyte, oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GDAP1	1,249

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GDAP1	Q8TB36	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Class I peroxisomal membrane protein import	1	519.1×	0.002	GDAP1

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
cellular response to vitamin D	1	1532.0×	0.002	GDAP1
mitochondrial fission	1	1053.2×	0.002	GDAP1
mitochondrial fusion	1	842.6×	0.002	GDAP1
obsolete protein targeting to mitochondrion	1	581.1×	0.002	GDAP1
response to retinoic acid	1	383.0×	0.003	GDAP1

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
GDAP1	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	GDAP1

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)
GDAP1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.