Charcot-Marie-Tooth disease dominant intermediate C

Summary

Charcot-Marie-Tooth disease dominant intermediate C (MONDO:0012012) is a disease caused by YARS1 (GenCC Strong), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: YARS1 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 540

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		35	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease dominant intermediate C
Mondo ID	MONDO:0012012
MeSH	C564257
OMIM	608323
Orphanet	100045
DOID	DOID:0110199
SNOMED CT	765746008
UMLS	C1842237
MedGen	334023
GARD	0012439
Is cancer (heuristic)	no

Also known as: autosomal dominant intermediate Charcot-Marie-Tooth disease type C · Charcot-Marie-Tooth disease caused by mutation in YARS · Charcot-Marie-Tooth disease dominant intermediate type C · Charcot-Marie-Tooth disease, dominant intermediate C · Charcot-Marie-Tooth disease, dominant Intermediate type C · CMTDIC · DI-CMTC · YARS Charcot-Marie-Tooth disease · YARS-related intermediate Charcot-Marie-Tooth neuropathy

Data availability: 540 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant intermediate Charcot-Marie-Tooth disease › Charcot-Marie-Tooth disease dominant intermediate C

Related subtypes (7): Charcot-Marie-Tooth disease dominant intermediate B, Charcot-Marie-Tooth Disease, axonal, type 2GG, Charcot-Marie-Tooth disease dominant intermediate D, Charcot-Marie-Tooth disease dominant intermediate E, Charcot-Marie-Tooth disease dominant intermediate F, autosomal dominant intermediate Charcot-Marie-Tooth disease with neuropathic pain, Charcot-Marie-Tooth disease, dominant intermediate A

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

540 retrieved; paginated sample, class counts are floors:

297 uncertain significance, 170 likely benign, 30 conflicting classifications of pathogenicity, 25 benign, 12 benign/likely benign, 3 pathogenic, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
187863	NM_003680.4(YARS1):c.241_242delinsAT (p.Asp81Ile)	YARS1	Pathogenic	no assertion criteria provided
243071	NM_003680.4(YARS1):c.586G>C (p.Glu196Gln)	YARS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6188	NM_003680.4(YARS1):c.121G>A (p.Gly41Arg)	YARS1	Pathogenic	criteria provided, single submitter
6189	NM_003680.4(YARS1):c.586G>A (p.Glu196Lys)	YARS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6190	NM_003680.4(YARS1):c.458_469del (p.Val153_Val156del)	YARS1	Pathogenic	no assertion criteria provided
662296	NM_003680.4(YARS1):c.499C>A (p.Pro167Thr)	YARS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
844705	NM_001540.5(HSPB1):c.172del (p.Leu58fs)	HSPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297155	NM_003680.4(YARS1):c.874T>G (p.Tyr292Asp)	LOC126805688	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297156	NM_003680.4(YARS1):c.685-11A>G	LOC126805688	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
464881	NM_003680.4(YARS1):c.795G>C (p.Lys265Asn)	LOC126805688	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1102663	NM_003680.4(YARS1):c.45C>T (p.Thr15=)	S100PBP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
863098	NM_003680.4(YARS1):c.40A>T (p.Ile14Phe)	S100PBP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1045888	NM_003680.4(YARS1):c.1276del (p.Asn425_Leu426insTer)	YARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1163138	NM_003680.4(YARS1):c.497A>G (p.Tyr166Cys)	YARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1681507	NM_003680.4(YARS1):c.835C>T (p.Arg279Ter)	YARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1681520	NM_003680.4(YARS1):c.620G>A (p.Arg207Gln)	YARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1681523	NM_003680.4(YARS1):c.587A>G (p.Glu196Gly)	YARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1700188	NM_003680.4(YARS1):c.290A>G (p.Tyr97Cys)	YARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
194050	NM_003680.4(YARS1):c.1464C>T (p.Phe488=)	YARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
284760	NM_003680.4(YARS1):c.510+10G>C	YARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297154	NM_003680.4(YARS1):c.946G>A (p.Ala316Thr)	YARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297157	NM_003680.4(YARS1):c.684+3A>G	YARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297161	NM_003680.4(YARS1):c.391C>T (p.Leu131=)	YARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
389313	NM_003680.4(YARS1):c.381-6C>T	YARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
415914	NM_003680.4(YARS1):c.1228G>A (p.Val410Met)	YARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
464873	NM_003680.4(YARS1):c.1291A>T (p.Met431Leu)	YARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
464876	NM_003680.4(YARS1):c.483G>C (p.Leu161=)	YARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
533461	NM_003680.4(YARS1):c.1549A>G (p.Ile517Val)	YARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
533466	NM_003680.4(YARS1):c.1048A>G (p.Met350Val)	YARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
567612	NM_003680.4(YARS1):c.1099C>T (p.Arg367Trp)	YARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
YARS1	Definitive	Autosomal dominant	Charcot-Marie-Tooth disease	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
YARS1	Orphanet:100045	Autosomal dominant intermediate Charcot-Marie-Tooth disease type C
ADPRS	Orphanet:694922	Childhood-onset stress-induced neurodegenerative ataxia-seizure syndrome
HSPB1	Orphanet:139525	Distal hereditary motor neuropathy type 2
HSPB1	Orphanet:99940	Autosomal dominant Charcot-Marie-Tooth disease type 2F

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
YARS1	HGNC:12840	ENSG00000134684	P54577	Tyrosine–tRNA ligase, cytoplasmic	gencc,clinvar
ADPRS	HGNC:21304	ENSG00000116863	Q9NX46	ADP-ribosylhydrolase ARH3	clinvar
S100PBP	HGNC:25768	ENSG00000116497	Q96BU1	S100P-binding protein	clinvar
HSPB1	HGNC:5246	ENSG00000106211	P04792	Heat shock protein beta-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
YARS1	Tyrosine–tRNA ligase, cytoplasmic	Tyrosine–tRNA ligase that catalyzes the attachment of tyrosine to tRNA(Tyr) in a two-step reaction: tyrosine is first activated by ATP to form Tyr-AMP and then transferred to the acceptor end of tRNA(Tyr).
ADPRS	ADP-ribosylhydrolase ARH3	ADP-ribosylhydrolase that preferentially hydrolyzes the scissile alpha-O-linkage attached to the anomeric C1’’ position of ADP-ribose and acts on different substrates, such as proteins ADP-ribosylated on serine and threonine, free poly(ADP…
HSPB1	Heat shock protein beta-1	Small heat shock protein which functions as a molecular chaperone probably maintaining denatured proteins in a folding-competent state.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

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)	2	6.0×	0.074
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
YARS1	Enzyme (other)	yes	6.1.1.1	aa-tRNA-synth_Ic, Tyr-tRNA-ligase, tRNA-bd_dom
ADPRS	Enzyme (other)	yes	3.2.1.143	Ribosyl_crysJ1, Ribosyl_crysJ1_sf, ADP-ribosylglycohydrolase
S100PBP	Other/Unknown	no		S100PBP
HSPB1	Other/Unknown	no		Alpha-crystallin/sHSP_animal, A-crystallin/Hsp20_dom, HSP20-like_chaperone

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
islet of Langerhans	1
left adrenal gland	1
right adrenal gland	1
endothelial cell	1
oviduct epithelium	1
right uterine tube	1
germinal epithelium of ovary	1
left testis	1
right testis	1
ascending aorta	1
lower esophagus mucosa	1
thoracic aorta	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
YARS1	290	ubiquitous	marker	islet of Langerhans, right adrenal gland, left adrenal gland
ADPRS	251	ubiquitous	marker	oviduct epithelium, right uterine tube, endothelial cell
S100PBP	270	ubiquitous	marker	right testis, left testis, germinal epithelium of ovary
HSPB1	299	ubiquitous	marker	lower esophagus mucosa, ascending aorta, thoracic aorta

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HSPB1	5,491
YARS1	4,793
S100PBP	733
ADPRS	580

Intra-cohort edges

A	B	Sources
ADPRS	HSPB1	intact

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ADPRS	Q9NX46	14
YARS1	P54577	8
HSPB1	P04792	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
S100PBP	Q96BU1	54.56

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Resolution of AP sites via the multiple-nucleotide patch replacement pathway	1	951.7×	0.015	ADPRS
POLB-Dependent Long Patch Base Excision Repair	1	423.0×	0.015	ADPRS
Resolution of Abasic Sites (AP sites)	1	380.7×	0.015	ADPRS
Base Excision Repair	1	237.9×	0.018	ADPRS
Cytosolic tRNA aminoacylation	1	146.4×	0.019	YARS1
Attenuation phase	1	135.9×	0.019	HSPB1
HSF1 activation	1	126.9×	0.019	HSPB1
HSF1-dependent transactivation	1	105.7×	0.020	HSPB1
tRNA Aminoacylation	1	95.2×	0.020	YARS1
AUF1 (hnRNP D0) binds and destabilizes mRNA	1	82.8×	0.020	HSPB1
Extra-nuclear estrogen signaling	1	56.8×	0.027	HSPB1
Regulation of HSF1-mediated heat shock response	1	46.4×	0.027	HSPB1
VEGFA-VEGFR2 Pathway	1	46.4×	0.027	HSPB1
MAPK6/MAPK4 signaling	1	45.3×	0.027	HSPB1
DNA Repair	1	32.8×	0.034	ADPRS
Translation	1	20.7×	0.051	YARS1
Metabolism of proteins	1	4.1×	0.223	YARS1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
tyrosyl-tRNA aminoacylation	1	5617.3×	0.001	YARS1
cellular response to superoxide	1	5617.3×	0.001	ADPRS
negative regulation of protein kinase C signaling	1	5617.3×	0.001	HSPB1
peptidyl-serine ADP-deribosylation	1	5617.3×	0.001	ADPRS
anterograde axonal protein transport	1	702.2×	0.008	HSPB1
intestinal epithelial structure maintenance	1	624.1×	0.008	HSPB1
regulation of protein phosphorylation	1	374.5×	0.009	HSPB1
base-excision repair, gap-filling	1	374.5×	0.009	ADPRS
negative regulation of necroptotic process	1	330.4×	0.009	ADPRS
positive regulation of endothelial cell chemotaxis	1	330.4×	0.009	HSPB1
negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway	1	312.1×	0.009	HSPB1
protein refolding	1	208.1×	0.012	HSPB1
cellular response to vascular endothelial growth factor stimulus	1	187.2×	0.012	HSPB1
regulation of canonical NF-kappaB signal transduction	1	160.5×	0.012	HSPB1
vascular endothelial growth factor receptor signaling pathway	1	160.5×	0.012	HSPB1
regulation of translational initiation	1	156.0×	0.012	HSPB1
response to starvation	1	156.0×	0.012	YARS1
response to heat	1	140.4×	0.012	HSPB1
positive regulation of blood vessel endothelial cell migration	1	130.6×	0.012	HSPB1
platelet aggregation	1	112.3×	0.014	HSPB1
response to unfolded protein	1	100.3×	0.015	HSPB1
positive regulation of interleukin-1 beta production	1	86.4×	0.016	HSPB1
regulation of autophagy	1	80.2×	0.017	HSPB1
positive regulation of tumor necrosis factor production	1	51.1×	0.025	HSPB1
response to virus	1	48.0×	0.026	HSPB1
positive regulation of angiogenesis	1	38.5×	0.031	HSPB1
protein folding	1	34.5×	0.033	HSPB1
DNA repair	1	21.3×	0.051	ADPRS
intracellular signal transduction	1	12.7×	0.082	HSPB1
negative regulation of apoptotic process	1	11.6×	0.087	HSPB1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
YARS1	CAPSAICIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
YARS1	2	4
HSPB1	1	2
ADPRS	0	0
S100PBP	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CAPSAICIN	4	YARS1
CRENOLANIB	3	YARS1
DORAMAPIMOD	2	HSPB1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
HSPB1	70	Binding:70
YARS1	16	Binding:16
ADPRS	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
YARS1	6.1.1.1	tyrosine-tRNA ligase
ADPRS	3.2.1.143	poly(ADP-ribose) glycohydrolase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

3 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)
CAPSAICIN	4	YARS1
CRENOLANIB	3	YARS1
DORAMAPIMOD	2	HSPB1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	YARS1
B	Phased (≥1) drug, not yet approved	1	HSPB1
C	Druggable family + PDB, no drug	1	ADPRS
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	S100PBP

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)
ADPRS	4	—
S100PBP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.