Charcot-Marie-Tooth disease, axonal, Type 2HH

Summary

Charcot-Marie-Tooth disease, axonal, Type 2HH (MONDO:0030458) is a disease caused by JAG1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: JAG1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 216

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease, axonal, Type 2HH
Mondo ID	MONDO:0030458
OMIM	619574
UMLS	C5562003
MedGen	1794213
GARD	0025568
Is cancer (heuristic)	no

Also known as: CMT2HH

Data availability: 216 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, axonal, Type 2HH

Related subtypes (23): Charcot-Marie-Tooth disease, Guadalajara neuronal type, Charcot-Marie-Tooth disease with ptosis and parkinsonism, Charcot-Marie-Tooth disease type 3, neuronopathy, distal hereditary motor, autosomal dominant 1, neuropathy, hereditary motor and sensory, type 6A, Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;, demyelinating hereditary motor and sensory neuropathy, intermediate Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 2, Charcot-Marie-Tooth disease type X, Charcot-Marie-Tooth disease type 4, Charcot-Marie-Tooth disease type 1, Charcot-Marie-Tooth disease, axonal, mitochondrial form, 1, Charcot-Marie-Tooth disease, axonal, type 2FF, Charcot-Marie-Tooth disease, demyelinating, IIA 1I, Charcot-Marie-Tooth disease, demyelinating, IIA 1H, Charcot-Marie-Tooth disease, axonal, IIa 2II, Charcot-Marie-Tooth disease, demyelinating, type 1G, Charcot-Marie-Tooth disease, demyelinating, type 1J, Charcot-Marie-tooth disease, axonal, type 2JJ, Charcot-Marie-Tooth disease, axonal, type 2KK, Charcot-Marie-Tooth disease, axonal, type 2LL, charcot-marie-tooth disease, axonal, type 2MM

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

216 retrieved; paginated sample, class counts are floors:

75 uncertain significance, 72 conflicting classifications of pathogenicity, 29 likely benign, 21 benign/likely benign, 10 pathogenic, 4 pathogenic/likely pathogenic, 3 benign, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1300241	NM_000214.3(JAG1):c.1731C>G (p.Ser577Arg)	JAG1	Pathogenic	criteria provided, single submitter
1300242	NM_000214.3(JAG1):c.1948T>C (p.Ser650Pro)	JAG1	Pathogenic	no assertion criteria provided
1455702	NM_000214.3(JAG1):c.1666G>T (p.Glu556Ter)	JAG1	Pathogenic	criteria provided, single submitter
213529	NM_000214.3(JAG1):c.439+1G>A	JAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
213538	NM_000214.3(JAG1):c.2230C>T (p.Arg744Ter)	JAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
234320	NM_000214.3(JAG1):c.703C>T (p.Arg235Ter)	JAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
2717767	NM_000214.3(JAG1):c.2999dup (p.Ala1001fs)	JAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280608	NM_000214.3(JAG1):c.311del (p.Gly104fs)	JAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382687	NM_000214.3(JAG1):c.2472C>A (p.Cys824Ter)	JAG1	Pathogenic	criteria provided, single submitter
598457	NM_000214.3(JAG1):c.1452_1453del (p.Cys484_Glu485delinsTer)	JAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7619	NM_000214.3(JAG1):c.550C>T (p.Arg184Cys)	JAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
7620	NM_000214.3(JAG1):c.551G>A (p.Arg184His)	JAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
7621	NM_000214.3(JAG1):c.2096_2100del (p.Gly699fs)	JAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
849005	NM_000214.3(JAG1):c.2172_2173dup (p.Asp725fs)	JAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1329612	NM_000214.3(JAG1):c.2113+1G>A	JAG1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3587091	NM_000214.3(JAG1):c.138dup (p.Gly47fs)	JAG1	Likely pathogenic	criteria provided, single submitter
1005101	NM_000214.3(JAG1):c.2911T>C (p.Ser971Pro)	JAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1011417	NM_000214.3(JAG1):c.2828C>T (p.Pro943Leu)	JAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1018280	NM_000214.3(JAG1):c.1465G>A (p.Asp489Asn)	JAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1037966	NM_000214.3(JAG1):c.349C>G (p.Arg117Gly)	JAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1043665	NM_000214.3(JAG1):c.1444G>A (p.Asp482Asn)	JAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1044935	NM_000214.3(JAG1):c.1321G>A (p.Gly441Ser)	JAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1046663	NM_000214.3(JAG1):c.978G>A (p.Glu326=)	JAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1047239	NM_000214.3(JAG1):c.3329A>G (p.Asn1110Ser)	JAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1051296	NM_000214.3(JAG1):c.3562G>A (p.Gly1188Ser)	JAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1060160	NM_000214.3(JAG1):c.2701C>A (p.Pro901Thr)	JAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1062934	NM_000214.3(JAG1):c.3398C>T (p.Thr1133Met)	JAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1099848	NM_000214.3(JAG1):c.2715C>T (p.His905=)	JAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1147881	NM_000214.3(JAG1):c.2497G>A (p.Ala833Thr)	JAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1358646	NM_000214.3(JAG1):c.1270G>A (p.Ala424Thr)	JAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 3 · 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
JAG1	Strong	Autosomal dominant	Charcot-Marie-Tooth disease, axonal, Type 2HH	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
JAG1	Orphanet:261600	Alagille syndrome due to 20p12 microdeletion
JAG1	Orphanet:261619	Alagille syndrome due to a JAG1 point mutation
JAG1	Orphanet:3303	Tetralogy of Fallot

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
JAG1	HGNC:6188	ENSG00000101384	P78504	Protein jagged-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
JAG1	Protein jagged-1	Ligand for multiple Notch receptors and involved in the mediation of Notch signaling.

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)
JAG1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, VWF_dom

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
blood vessel layer	1
skin of hip	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
JAG1	297	ubiquitous	marker	upper leg skin, skin of hip, blood vessel layer

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
JAG1	4,405

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
JAG1	P78504	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 34. 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
Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	2855.0×	0.005	JAG1
Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	1631.4×	0.005	JAG1
Signaling by NOTCH1 HD Domain Mutants in Cancer	1	1268.9×	0.005	JAG1
NOTCH4 Activation and Transmission of Signal to the Nucleus	1	1038.2×	0.005	JAG1
Nephron development	1	878.5×	0.005	JAG1
RUNX3 regulates NOTCH signaling	1	815.7×	0.005	JAG1
Kidney development	1	815.7×	0.005	JAG1
Constitutive Signaling by NOTCH1 HD Domain Mutants	1	761.3×	0.005	JAG1
Signaling by NOTCH2	1	713.8×	0.005	JAG1
Signaling by NOTCH3	1	519.1×	0.005	JAG1
Signaling by NOTCH4	1	496.5×	0.005	JAG1
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	475.8×	0.005	JAG1
NOTCH2 Activation and Transmission of Signal to the Nucleus	1	439.2×	0.005	JAG1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1	407.9×	0.005	JAG1
Signaling by NOTCH1 in Cancer	1	407.9×	0.005	JAG1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1	407.9×	0.005	JAG1
Signaling by NOTCH1	1	356.9×	0.005	JAG1
Activated NOTCH1 Transmits Signal to the Nucleus	1	356.9×	0.005	JAG1
Transcriptional regulation by RUNX3	1	271.9×	0.007	JAG1
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	196.9×	0.008	JAG1
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	196.9×	0.008	JAG1
Signaling by NOTCH	1	175.7×	0.009	JAG1
RAC3 GTPase cycle	1	119.0×	0.012	JAG1
RAC1 GTPase cycle	1	61.1×	0.023	JAG1
RHO GTPase cycle	1	60.1×	0.023	JAG1
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.023	JAG1
Signaling by Rho GTPases	1	34.2×	0.036	JAG1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	33.5×	0.036	JAG1
RNA Polymerase II Transcription	1	22.5×	0.052	JAG1
Gene expression (Transcription)	1	17.8×	0.064	JAG1

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
endocardial cushion cell development	1	16852.0×	0.001	JAG1
loop of Henle development	1	8426.0×	0.001	JAG1
cardiac neural crest cell development involved in outflow tract morphogenesis	1	5617.3×	0.001	JAG1
distal tubule development	1	5617.3×	0.001	JAG1
inhibition of neuroepithelial cell differentiation	1	4213.0×	0.001	JAG1
ciliary body morphogenesis	1	4213.0×	0.001	JAG1
positive regulation of cardiac epithelial to mesenchymal transition	1	4213.0×	0.001	JAG1
negative regulation of endothelial cell differentiation	1	3370.4×	0.001	JAG1
positive regulation of myeloid cell differentiation	1	3370.4×	0.001	JAG1
pulmonary artery morphogenesis	1	2808.7×	0.002	JAG1
neuroendocrine cell differentiation	1	2407.4×	0.002	JAG1
nephron development	1	1872.4×	0.002	JAG1
morphogenesis of an epithelial sheet	1	1685.2×	0.002	JAG1
podocyte development	1	1532.0×	0.002	JAG1
cardiac right ventricle morphogenesis	1	1404.3×	0.002	JAG1
response to muramyl dipeptide	1	1404.3×	0.002	JAG1
inner ear auditory receptor cell differentiation	1	1203.7×	0.002	JAG1
cardiac septum morphogenesis	1	1203.7×	0.002	JAG1
endothelial cell differentiation	1	1123.5×	0.002	JAG1
T cell mediated immunity	1	991.3×	0.002	JAG1
negative regulation of cell-cell adhesion	1	991.3×	0.002	JAG1
cell fate determination	1	936.2×	0.002	JAG1
pulmonary valve morphogenesis	1	936.2×	0.002	JAG1
regulation of epithelial cell proliferation	1	936.2×	0.002	JAG1
negative regulation of cell-matrix adhesion	1	887.0×	0.002	JAG1
aorta morphogenesis	1	887.0×	0.002	JAG1
myoblast differentiation	1	842.6×	0.002	JAG1
negative regulation of stem cell differentiation	1	842.6×	0.002	JAG1
neuronal stem cell population maintenance	1	674.1×	0.002	JAG1
aortic valve morphogenesis	1	432.1×	0.003	JAG1

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
JAG1	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
JAG1	1	Binding:1

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	JAG1

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)
JAG1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.