Charcot-Marie-Tooth disease type 2D

Summary

Charcot-Marie-Tooth disease type 2D (MONDO:0011091) is a disease caused by GARS1 (GenCC Strong), with 1 cohort gene and 2 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GARS1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 108
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		44	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease type 2D
Mondo ID	MONDO:0011091
MeSH	C537993
OMIM	601472
Orphanet	99938
DOID	DOID:0110164
ICD-11	1617529678
NCIT	C122659
SNOMED CT	717011006
UMLS	C1832274
MedGen	316946
GARD	0001251
Is cancer (heuristic)	no

Also known as: autosomal dominant Charcot-Marie-Tooth disease type 2D · Charcot Marie Tooth disease type 2D · Charcot-Marie-Tooth disease type 2 caused by mutation in GARS · Charcot-Marie-Tooth disease, axonal, type 2D · Charcot-Marie-Tooth disease, type 2D · CMT 2D · CMT2D · GARS Charcot-Marie-Tooth disease type 2

Data availability: 108 ClinVar variants · 3 GenCC gene-disease records · 7 cell lines.

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 type 2D

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

108 retrieved; paginated sample, class counts are floors:

34 uncertain significance, 29 conflicting classifications of pathogenicity, 17 benign/likely benign, 16 benign, 7 pathogenic, 2 not provided, 2 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1342184	NM_002047.4(GARS1):c.1007C>A (p.Pro336His)	GARS1	Pathogenic	no assertion criteria provided
410314	NM_002047.4(GARS1):c.1415A>G (p.His472Arg)	GARS1	Pathogenic	criteria provided, multiple submitters, no conflicts
476747	NM_002047.4(GARS1):c.1000A>T (p.Ile334Phe)	GARS1	Pathogenic	criteria provided, multiple submitters, no conflicts
543227	NM_002047.4(GARS1):c.1001T>A (p.Ile334Asn)	GARS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
661670	NM_002047.4(GARS1):c.979G>A (p.Gly327Arg)	GARS1	Pathogenic	criteria provided, multiple submitters, no conflicts
9204	NM_002047.4(GARS1):c.880G>C (p.Gly294Arg)	GARS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9205	NM_002047.4(GARS1):c.548T>C (p.Leu183Pro)	GARS1	Pathogenic	criteria provided, single submitter
9207	NM_002047.4(GARS1):c.1738G>C (p.Gly580Arg)	GARS1	Pathogenic	criteria provided, single submitter
984908	NM_002047.4(GARS1):c.794C>A (p.Ser265Tyr)	GARS1	Pathogenic	no assertion criteria provided
216930	NM_002047.4(GARS1):c.998A>T (p.Glu333Val)	GARS1	Likely pathogenic	criteria provided, single submitter
194367	NM_002047.4(GARS1):c.1716G>A (p.Pro572=)	GARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
209157	NM_002047.4(GARS1):c.1904C>T (p.Ser635Leu)	GARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
216550	NM_002047.4(GARS1):c.1852G>A (p.Val618Ile)	GARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
245685	NM_002047.4(GARS1):c.302G>A (p.Arg101His)	GARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
360003	NM_002047.4(GARS1):c.384G>A (p.Leu128=)	GARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
360005	NM_002047.4(GARS1):c.764C>T (p.Ala255Val)	GARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
360006	NM_002047.4(GARS1):c.765G>A (p.Ala255=)	GARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
360008	NM_002047.4(GARS1):c.882-15T>G	GARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
360009	NM_002047.4(GARS1):c.882-4A>G	GARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
360011	NM_002047.4(GARS1):c.1100A>G (p.Asn367Ser)	GARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
360014	NM_002047.4(GARS1):c.1478A>G (p.Asn493Ser)	GARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
360016	NM_002047.4(GARS1):c.1809+14T>C	GARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
360018	NM_002047.4(GARS1):c.2211C>T (p.Ile737=)	GARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
410311	NM_002047.4(GARS1):c.262C>G (p.Gln88Glu)	GARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
422016	NM_002047.4(GARS1):c.253A>G (p.Lys85Glu)	GARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
431819	NM_002047.4(GARS1):c.562G>A (p.Val188Ile)	GARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
447371	NM_002047.4(GARS1):c.1171C>T (p.Arg391Cys)	GARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
585901	NM_002047.4(GARS1):c.2159A>C (p.Glu720Ala)	GARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
637502	NM_002047.4(GARS1):c.1031+1G>A	GARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
637542	NM_002047.4(GARS1):c.631T>C (p.Cys211Arg)	GARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 2 · 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
GARS1	Strong	Autosomal dominant	Charcot-Marie-Tooth disease type 2D	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GARS1	Orphanet:139536	Distal hereditary motor neuropathy type 5
GARS1	Orphanet:99938	Autosomal dominant Charcot-Marie-Tooth disease type 2D

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
GARS1	HGNC:4162	ENSG00000106105	P41250	Glycine–tRNA ligase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GARS1	Glycine–tRNA ligase	Catalyzes the ATP-dependent ligation of glycine to the 3’-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (Gly-AMP).

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)
GARS1	Enzyme (other)	yes	6.1.1.14	WHEP-TRS_dom, aa-tRNA-synt_IIb, tRNA-synt_gly

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
cartilage tissue	1
lateral nuclear group of thalamus	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GARS1	293	ubiquitous	marker	secondary oocyte, cartilage tissue, lateral nuclear group of thalamus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GARS1	2,426

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GARS1	P41250	14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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×	0.002	GARS1
Cytosolic tRNA aminoacylation	1	439.2×	0.002	GARS1

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 glycyl-tRNA aminoacylation	1	8426.0×	3e-04	GARS1
diadenosine tetraphosphate biosynthetic process	1	5617.3×	3e-04	GARS1
tRNA aminoacylation for protein translation	1	842.6×	0.001	GARS1

Therapeutics

Drug target analysis

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

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
GARS1	1	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CRENOLANIB	3	GARS1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
GARS1	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GARS1	6.1.1.14	glycine-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

1 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.

Compound	Max phase	Cohort target (bioactivity)
CRENOLANIB	3	GARS1

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	1	GARS1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07226297	PHASE1/PHASE2	ENROLLING_BY_INVITATION	Personalized Antisense Oligonucleotide for A Single Participant With GARS1 Gene Mutation Associated With Charcot-Marie-Tooth Disease Type 2D (CMT2D)
NCT05902351	Not specified	RECRUITING	Natural History Study for Charcot Marie Tooth Disease