Charcot-Marie-Tooth disease, axonal, type 2LL

Summary

Charcot-Marie-Tooth disease, axonal, type 2LL (MONDO:0980969) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease, axonal, type 2LL
Mondo ID	MONDO:0980969
OMIM	621485
Is cancer (heuristic)	no

Data availability: 5 ClinVar variants.

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 2LL

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, axonal, Type 2HH, 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 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

5 retrieved; paginated sample, class counts are floors:

5 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1062	NM_018122.5(DARS2):c.492+2T>C	DARS2	Pathogenic	criteria provided, multiple submitters, no conflicts
4688052	NM_018122.5(DARS2):c.1006C>T (p.Arg336Cys)	DARS2	Pathogenic	no assertion criteria provided
4688053	NM_018122.5(DARS2):c.713C>T (p.Ser238Phe)	DARS2	Pathogenic	criteria provided, single submitter
4688054	NM_018122.5(DARS2):c.74del (p.Ile25fs)	DARS2	Pathogenic	no assertion criteria provided
4688055	NM_018122.5(DARS2):c.1508C>T (p.Pro503Leu)	DARS2	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DARS2	Orphanet:137898	Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome

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
DARS2	HGNC:25538	ENSG00000117593	Q6PI48	Aspartate–tRNA ligase, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DARS2	Aspartate–tRNA ligase, mitochondrial	Catalyzes the attachment of aspartate to tRNA(Asp) in a two-step reaction: aspartate is first activated by ATP to form Asp-AMP and then transferred to the acceptor end of tRNA(Asp).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DARS2	Enzyme (other)	yes	6.1.1.12	Asp/Asn-tRNA-synth_IIb, GAD-like_sf, Aa-tRNA-synt_II

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
adrenal tissue	1
primordial germ cell in gonad	1
rectum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DARS2	180	ubiquitous	marker	primordial germ cell in gonad, rectum, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DARS2	3,288

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DARS2	Q6PI48	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Mitochondrial tRNA aminoacylation	1	519.1×	0.007	DARS2
tRNA Aminoacylation	1	285.5×	0.007	DARS2
Translation	1	62.1×	0.021	DARS2
Metabolism of proteins	1	12.4×	0.081	DARS2

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
mitochondrial asparaginyl-tRNA aminoacylation	1	16852.0×	1e-04	DARS2
aspartyl-tRNA aminoacylation	1	8426.0×	1e-04	DARS2
tRNA aminoacylation	1	8426.0×	1e-04	DARS2

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
DARS2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DARS2	6.1.1.12	aspartate-tRNA ligase

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	1	DARS2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
DARS2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.