Charcot-Marie-Tooth disease axonal type 2N

Summary

Charcot-Marie-Tooth disease axonal type 2N (MONDO:0013212) is a disease caused by AARS1 (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: AARS1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 121
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		28	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease axonal type 2N
Mondo ID	MONDO:0013212
MeSH	C567653
OMIM	613287
Orphanet	228174
DOID	DOID:0110177
SNOMED CT	719515001
UMLS	C2750090
MedGen	413754
GARD	0012429
Is cancer (heuristic)	no

Also known as: AARS Charcot-Marie-Tooth disease type 2 · autosomal dominant Charcot-Marie-Tooth disease type 2N · Charcot-Marie-Tooth disease type 2 caused by mutation in AARS · Charcot-Marie-Tooth disease type 2N · Charcot-Marie-Tooth disease, axonal, type 2N · CMT2N

Data availability: 121 ClinVar variants · 4 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 2N

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 2K, Charcot-Marie-Tooth disease axonal type 2L, Charcot-Marie-Tooth disease type 2A2, giant axonal neuropathy 2, 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

121 retrieved; paginated sample, class counts are floors:

41 uncertain significance, 34 conflicting classifications of pathogenicity, 20 benign/likely benign, 9 likely benign, 6 benign, 5 likely pathogenic, 3 pathogenic, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1323797	NM_001605.3(AARS1):c.1009G>A (p.Glu337Lys)	AARS1	Pathogenic	criteria provided, single submitter
1682320	NM_001605.3(AARS1):c.312G>A (p.Trp104Ter)	AARS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685482	NM_001605.3(AARS1):c.977G>C (p.Arg326Pro)	AARS1	Pathogenic	criteria provided, single submitter
2231150	NM_001605.3(AARS1):c.966T>G (p.Tyr322Ter)	AARS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3774576	NM_001605.3(AARS1):c.2160_2169del (p.Glu721fs)	AARS1	Pathogenic	criteria provided, single submitter
8466	NM_001605.3(AARS1):c.986G>A (p.Arg329His)	AARS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190102	NM_001605.3(AARS1):c.242A>C (p.Lys81Thr)	AARS1	Likely pathogenic	criteria provided, single submitter
2504064	NM_001605.3(AARS1):c.1815C>G (p.His605Gln)	AARS1	Likely pathogenic	criteria provided, single submitter
2584743	NM_001605.3(AARS1):c.479+1G>T	AARS1	Likely pathogenic	criteria provided, single submitter
4795854	NM_001605.3(AARS1):c.277dup (p.Tyr93fs)	AARS1	Likely pathogenic	criteria provided, single submitter
549673	NM_001605.3(AARS1):c.328T>C (p.Phe110Leu)	AARS1	Likely pathogenic	no assertion criteria provided
155734	NM_001605.3(AARS1):c.2185C>T (p.Arg729Trp)	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1685481	NM_001605.3(AARS1):c.2192C>G (p.Ser731Trp)	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
190103	NM_001605.3(AARS1):c.2251A>G (p.Arg751Gly)	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
194936	NM_001605.3(AARS1):c.2521-3C>T	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
197729	NM_001605.3(AARS1):c.600C>T (p.Ala200=)	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
245983	NM_001605.3(AARS1):c.518A>G (p.Asp173Gly)	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
246063	NM_001605.3(AARS1):c.2186G>A (p.Arg729Gln)	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
246158	NM_001605.3(AARS1):c.1481G>T (p.Ser494Ile)	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
30155	NM_001605.3(AARS1):c.211A>T (p.Asn71Tyr)	AARS1	Conflicting classifications of pathogenicity	no assertion criteria provided
320324	NM_001605.3(AARS1):c.2732A>G (p.Asn911Ser)	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
320328	NM_001605.3(AARS1):c.2580G>A (p.Leu860=)	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
320329	NM_001605.3(AARS1):c.2421C>A (p.Ile807=)	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
320334	NM_001605.3(AARS1):c.2109G>C (p.Val703=)	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
320339	NM_001605.3(AARS1):c.1596C>A (p.Thr532=)	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
320340	NM_001605.3(AARS1):c.1587G>A (p.Leu529=)	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
320341	NM_001605.3(AARS1):c.1493-7T>C	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
320344	NM_001605.3(AARS1):c.1253A>G (p.Tyr418Cys)	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
320346	NM_001605.3(AARS1):c.962+15C>T	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
320347	NM_001605.3(AARS1):c.904G>A (p.Ala302Thr)	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 4 · 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
AARS1	Definitive	Autosomal dominant	Charcot-Marie-Tooth disease axonal type 2N	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AARS1	Orphanet:228174	Autosomal dominant Charcot-Marie-Tooth disease type 2N
AARS1	Orphanet:33364	Trichothiodystrophy
AARS1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
ATL3	Orphanet:36386	Hereditary sensory and autonomic neuropathy type 1

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
AARS1	HGNC:20	ENSG00000090861	P49588	Alanine–tRNA ligase, cytoplasmic	gencc,clinvar
ATL3	HGNC:24526	ENSG00000184743	Q6DD88	Atlastin-3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AARS1	Alanine–tRNA ligase, cytoplasmic	Catalyzes the attachment of alanine to tRNA(Ala) in a two-step reaction: alanine is first activated by ATP to form Ala-AMP and then transferred to the acceptor end of tRNA(Ala).
ATL3	Atlastin-3	Atlastin-3 (ATL3) is a membrane-anchored GTPase that mediates the GTP-dependent fusion of endoplasmic reticulum (ER) membranes, maintaining the continuous ER network.

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)
AARS1	Other/Unknown	no		Ala-tRNA-lgiase_IIc, DHHA1_dom, Transl_B-barrel_sf
ATL3	Other/Unknown	no		Guanylate-bd/ATL_C, Guanylate-bd_N, P-loop_NTPase

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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
endometrium epithelium	1
frontal pole	1
type B pancreatic cell	1
layer of synovial tissue	1
saphenous vein	1
upper arm skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AARS1	301	ubiquitous	marker	endometrium epithelium, type B pancreatic cell, frontal pole
ATL3	255	ubiquitous	marker	upper arm skin, saphenous vein, layer of synovial tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AARS1	3,074
ATL3	1,536

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AARS1	P49588	6
ATL3	Q6DD88	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Cytosolic tRNA aminoacylation	1	439.2×	0.007	AARS1
tRNA Aminoacylation	1	285.5×	0.007	AARS1
Translation	1	62.1×	0.021	AARS1
Metabolism of proteins	1	12.4×	0.081	AARS1

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
regulation of cytoplasmic translational fidelity	1	8426.0×	0.002	AARS1
alanyl-tRNA aminoacylation	1	4213.0×	0.002	AARS1
endoplasmic reticulum membrane fusion	1	1685.2×	0.003	ATL3
endoplasmic reticulum tubular network membrane organization	1	1053.2×	0.004	ATL3
cerebellar Purkinje cell layer development	1	766.0×	0.004	AARS1
negative regulation of signal transduction by p53 class mediator	1	601.9×	0.004	AARS1
positive regulation of hippo signaling	1	526.6×	0.004	AARS1
tRNA aminoacylation for protein translation	1	421.3×	0.004	AARS1
tRNA processing	1	421.3×	0.004	AARS1
tRNA modification	1	300.9×	0.005	AARS1
endoplasmic reticulum organization	1	210.7×	0.006	ATL3
neuromuscular process controlling balance	1	165.2×	0.008	AARS1
neuron apoptotic process	1	92.6×	0.012	AARS1
protein homooligomerization	1	61.1×	0.017	ATL3
negative regulation of neuron apoptotic process	1	55.4×	0.018	AARS1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
AARS1	0	0
ATL3	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
AARS1	2	Binding:2
ATL3	1	Binding:1

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	AARS1, ATL3

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)
AARS1	2	—
ATL3	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05902351	Not specified	RECRUITING	Natural History Study for Charcot Marie Tooth Disease