Charcot-Marie-Tooth disease axonal type 2K

Summary

Charcot-Marie-Tooth disease axonal type 2K (MONDO:0011916) is a disease caused by GDAP1 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: GDAP1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 102
• Phenotypes (HPO): 37

Clinical features

Signs & symptoms

Clinical features (HPO)

37 HPO clinical features (Orphanet curated; top 37 by frequency):

HPO ID	Term	Frequency
HP:0000764	Peripheral axonal degeneration	Very frequent (80-99%)
HP:0002495	Impaired vibratory sensation	Very frequent (80-99%)
HP:0002936	Distal sensory impairment	Very frequent (80-99%)
HP:0003202	Skeletal muscle atrophy	Very frequent (80-99%)
HP:0003447	Axonal loss	Very frequent (80-99%)
HP:0007141	Sensorimotor neuropathy	Very frequent (80-99%)
HP:0007249	Decreased number of small peripheral myelinated nerve fibers	Very frequent (80-99%)
HP:0007267	Chronic axonal neuropathy	Very frequent (80-99%)
HP:0007328	Impaired pain sensation	Very frequent (80-99%)
HP:0008959	Distal upper limb muscle weakness	Very frequent (80-99%)
HP:0008994	Proximal muscle weakness in lower limbs	Very frequent (80-99%)
HP:0008997	Proximal muscle weakness in upper limbs	Very frequent (80-99%)
HP:0009053	Distal lower limb muscle weakness	Very frequent (80-99%)
HP:0010830	Impaired tactile sensation	Very frequent (80-99%)
HP:0011096	Peripheral demyelination	Very frequent (80-99%)
HP:0000925	Abnormality of the vertebral column	Frequent (30-79%)
HP:0001171	Split hand	Frequent (30-79%)
HP:0001284	Areflexia	Frequent (30-79%)
HP:0001315	Reduced tendon reflexes	Frequent (30-79%)
HP:0001371	Flexion contracture	Frequent (30-79%)
HP:0001604	Vocal cord paresis	Frequent (30-79%)
HP:0001609	Hoarse voice	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0001762	Talipes equinovarus	Frequent (30-79%)
HP:0002317	Unsteady gait	Frequent (30-79%)
HP:0002359	Frequent falls	Frequent (30-79%)
HP:0002505	Loss of ambulation	Frequent (30-79%)
HP:0003731	Quadriceps muscle weakness	Frequent (30-79%)
HP:0006858	Impaired distal proprioception	Frequent (30-79%)
HP:0007233	Clusters of axonal regeneration	Frequent (30-79%)
HP:0008954	Intrinsic hand muscle atrophy	Frequent (30-79%)
HP:0011727	Peroneal muscle weakness	Frequent (30-79%)
HP:0030237	Hand muscle weakness	Frequent (30-79%)
HP:0031629	Impaired tandem gait	Frequent (30-79%)
HP:0000765	Abnormal thorax morphology	Occasional (5-29%)
HP:0001270	Motor delay	Occasional (5-29%)
HP:0000762	Decreased nerve conduction velocity	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease axonal type 2K
Mondo ID	MONDO:0011916
OMIM	607831
Orphanet	101097
DOID	DOID:0110167
SNOMED CT	725047007
UMLS	C1842983
MedGen	375064
GARD	0012448
Is cancer (heuristic)	no

Also known as: ARCMT2K · autosomal recessive axonal Charcot-Marie-Tooth disease type 2K · autosomal recessive axonal CMT4C4 · autosomal recessive Charcot-Marie-Tooth disease with hoarseness · Charcot-Marie-Tooth disease, axonal, autosomal dominant, type 2K · Charcot-Marie-Tooth disease, axonal, type 2K · CMT2K

Data availability: 102 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 axonal type 2K

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

102 retrieved; paginated sample, class counts are floors:

37 uncertain significance, 20 pathogenic, 17 conflicting classifications of pathogenicity, 13 pathogenic/likely pathogenic, 9 likely pathogenic, 4 benign, 1 uncertain significance/vus-high, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
424778	NM_018972.2(GDAP1):c.[347T>C];[62delA]		Pathogenic	criteria provided, single submitter
1072856	NM_018972.4(GDAP1):c.577A>T (p.Lys193Ter)	GDAP1	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
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
406137	NM_018972.4(GDAP1):c.579del (p.Lys193fs)	GDAP1	Pathogenic	criteria provided, single submitter
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
4199	NM_018972.4(GDAP1):c.469A>C (p.Thr157Pro)	GDAP1	Pathogenic	criteria provided, single submitter
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
449535	NM_018972.4(GDAP1):c.929G>A (p.Arg310Gln)	GDAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
50557	NM_018972.4(GDAP1):c.467C>G (p.Ala156Gly)	GDAP1	Pathogenic	criteria provided, single submitter
50558	NM_018972.4(GDAP1):c.368A>G (p.His123Arg)	GDAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
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
637119	NM_018972.4(GDAP1):c.445G>T (p.Asp149Tyr)	GDAP1	Pathogenic	criteria provided, single submitter
637122	NM_018972.4(GDAP1):c.349dup (p.Tyr117fs)	GDAP1	Pathogenic	criteria provided, single submitter
637126	NM_018972.4(GDAP1):c.558del (p.Ile186fs)	GDAP1	Pathogenic	criteria provided, single submitter
637127	NM_018972.4(GDAP1):c.840del (p.Tyr279_Tyr280insTer)	GDAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
637452	NM_018972.4(GDAP1):c.311-1G>A	GDAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

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

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GDAP1	HGNC:15968	ENSG00000104381	Q8TB36	Ganglioside-induced differentiation-associated protein 1	gencc,clinvar
JPH1	HGNC:14201	ENSG00000104369	Q9HDC5	Junctophilin-1	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.
JPH1	Junctophilin-1	Junctophilins contribute to the formation of junctional membrane complexes (JMCs) which link the plasma membrane with the endoplasmic or sarcoplasmic reticulum in excitable cells.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

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
JPH1	Other/Unknown	no		MORN, Junctophilin

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endothelial cell	1
oocyte	1
secondary oocyte	1
quadriceps femoris	1
tibialis anterior	1
vastus lateralis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GDAP1	244	ubiquitous	yes	endothelial cell, secondary oocyte, oocyte
JPH1	213	broad	marker	quadriceps femoris, vastus lateralis, tibialis anterior

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
JPH1	1,646
GDAP1	1,249

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GDAP1	Q8TB36	8
JPH1	Q9HDC5	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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 2 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	766.0×	0.004	GDAP1
regulation of cardiac muscle contraction by calcium ion signaling	1	648.1×	0.004	JPH1
calcium ion transport into cytosol	1	601.9×	0.004	JPH1
mitochondrial fission	1	526.6×	0.004	GDAP1
mitochondrial fusion	1	421.3×	0.004	GDAP1
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	337.0×	0.004	JPH1
obsolete protein targeting to mitochondrion	1	290.6×	0.004	GDAP1
response to retinoic acid	1	191.5×	0.006	GDAP1
muscle organ development	1	83.4×	0.012	JPH1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
JPH1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	GDAP1, JPH1

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
GDAP1	0	—
JPH1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.