Charcot-Marie-Tooth disease

Summary

Charcot-Marie-Tooth disease (MONDO:0015626) is a disease (an umbrella term covering 24 Mondo subtypes) caused by variants in FGD4, FIG4, MPZ, and 6 other genes, with 75 cohort genes and 59 clinical trials. The dominant Reactome pathway is EGR2 and SOX10-mediated initiation of Schwann cell myelination (7 cohort genes). Top therapeutic interventions include epalrestat, mexiletine, and sorbitol.

At a glance

• Prevalence: 1-5 / 10 000 (Spain) [Orphanet-validated]
• Causal genes: FGD4 (GenCC Definitive), FIG4 (GenCC Definitive), MPZ (GenCC Definitive), NEFL (GenCC Definitive) (+5 more)
• Umbrella term: 24 Mondo subtypes
• Cohort genes: 75
• ClinVar variants: 3,247
• Clinical trials: 59

Clinical features

Epidemiology

Prevalence records

11 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	28.2	Spain	Validated
Point prevalence	1-5 / 10 000	17.5	Italy	Validated
Point prevalence	1-9 / 100 000	6.1	Denmark	Validated
Point prevalence	1-5 / 10 000	12	Iceland	Validated
Point prevalence	1-5 / 10 000	10.8	Japan	Validated
Point prevalence	1-5 / 10 000	16	Cyprus	Validated
Point prevalence	1-9 / 100 000	9.7	Serbia	Validated
Point prevalence	1-5 / 10 000	25	Europe	Not yet validated
Point prevalence	1-5 / 10 000	15.95	United Kingdom	Not yet validated
Point prevalence	6-9 / 10 000	61	Norway	Not yet validated
Point prevalence	1-5 / 10 000	19.55	Sweden	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease
Mondo ID	MONDO:0015626
MeSH	D002607
OMIM	118220
Orphanet	166
DOID	DOID:10595
NCIT	C75467
UMLS	C0007959
MedGen	2980
GARD	0006034
MedDRA	10034699
NORD	919
Is cancer (heuristic)	no

Also known as: Charcot Marie Tooth disease · Charcot Marie Tooth muscular atrophy · Charcot-Marie-Tooth disease · Charcot-Marie-Tooth hereditary neuropathy · CMT · CMT/HMSN · hereditary motor and sensory neuropathy · hereditary sensorimotor neuropathy · peroneal muscular atrophy

Data availability: 3,247 ClinVar variants · 23 GenCC gene-disease records · 39 cell lines.

Disease family

An umbrella term covering 24 Mondo subtypes.

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

Related subtypes (64): giant axonal neuropathy, Finnish type amyloidosis, familial amyloid neuropathy, carpal tunnel syndrome, congenital trigeminal anesthesia, familial recurrent peripheral facial palsy, meralgia paraesthetica, familial, amyotrophic neuralgia, hereditary neuropathy with liability to pressure palsies, abetalipoproteinemia, VPS13A-related neurodegenerative disease, mitochondrial DNA depletion syndrome 4a, oxoglutaricaciduria, cerebrotendinous xanthomatosis, Chediak-Higashi syndrome, homocystinuria due to methylene tetrahydrofolate reductase deficiency, Krabbe disease, beta-mannosidosis, biotinidase deficiency, Leigh syndrome, hereditary sensory and autonomic neuropathy with spastic paraplegia, ornithine aminotransferase deficiency, adult polyglucosan body disease, Sandhoff disease, Tay-Sachs disease, methylmalonic aciduria and homocystinuria type cblC, familial isolated deficiency of vitamin E, Kearns-Sayre syndrome, NARP syndrome, Charcot-Marie-Tooth disease type 5, hereditary motor and sensory neuropathy, Okinawa type, fumaric aciduria, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, Niemann-Pick disease type B, long chain 3-hydroxyacyl-CoA dehydrogenase deficiency, primary CD59 deficiency, PHARC syndrome, progressive demyelinating neuropathy with bilateral striatal necrosis, cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome, ataxia - oculomotor apraxia type 4, adrenomyeloneuropathy, neuropathy with hearing impairment, hereditary motor and sensory neuropathy, hereditary sensory and autonomic neuropathy, infantile axonal neuropathy, mitochondrial neurogastrointestinal encephalomyopathy, attenuated Chédiak-Higashi syndrome, coenzyme Q10 deficiency, familial episodic pain syndrome, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, metachromatic leukodystrophy, distal hereditary motor neuropathy, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2, proximal spinal muscular atrophy, pyruvate dehydrogenase deficiency, peroxisome biogenesis disorder, neurodegeneration with brain iron accumulation 2A, neuropathy, congenital hypomelinating, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, EMILIN-1-related connective tissue disease, PRPS1 deficiency disorder, neuropathy, hereditary sensory and autonomic, type IId, peripheral motor neuropathy, childhood-onset, biotin-responsive

Subtypes (24): 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 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

600 retrieved; paginated sample, class counts are floors:

168 conflicting classifications of pathogenicity, 116 benign/likely benign, 112 benign, 68 uncertain significance, 55 pathogenic, 51 pathogenic/likely pathogenic, 16 likely benign, 14 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
11795	NM_000052.7(ATP7A):c.4156C>T (p.Pro1386Ser)	ATP7A	Pathogenic	criteria provided, single submitter
183041	NM_006736.6(DNAJB2):c.229+1G>A	DNAJB2	Pathogenic	criteria provided, single submitter
217886	NM_006736.6(DNAJB2):c.352+1G>A	DNAJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
1360406	NM_001939.3(DRP2):c.1294G>T (p.Glu432Ter)	DRP2	Pathogenic	criteria provided, multiple submitters, no conflicts
16752	NM_000399.5(EGR2):c.1075C>T (p.Arg359Trp)	EGR2	Pathogenic	criteria provided, multiple submitters, no conflicts
1722	NM_014845.6(FIG4):c.294del (p.Phe98fs)	FIG4	Pathogenic	criteria provided, single submitter
1724	NM_014845.6(FIG4):c.1043_1050del (p.Asp348fs)	FIG4	Pathogenic	criteria provided, single submitter
254668	NM_014845.6(FIG4):c.759del (p.Phe254fs)	FIG4	Pathogenic	criteria provided, multiple submitters, no conflicts
220379	NM_018972.4(GDAP1):c.579+1G>A	GDAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
245608	NM_018972.4(GDAP1):c.769C>T (p.Arg257Ter)	GDAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10433	NM_000166.6(GJB1):c.415G>A (p.Val139Met)	GJB1	Pathogenic	criteria provided, multiple submitters, no conflicts
10435	NM_000166.6(GJB1):c.658C>T (p.Arg220Ter)	GJB1	Pathogenic	criteria provided, multiple submitters, no conflicts
10437	NM_000166.6(GJB1):c.467T>G (p.Leu156Arg)	GJB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10441	NM_000166.6(GJB1):c.283G>A (p.Val95Met)	GJB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10444	NM_000166.6(GJB1):c.254C>G (p.Ser85Cys)	GJB1	Pathogenic	criteria provided, single submitter
10446	NM_000166.6(GJB1):c.164C>T (p.Thr55Ile)	GJB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188136	NM_000166.6(GJB1):c.116C>T (p.Ala39Val)	GJB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188174	NM_000166.6(GJB1):c.425G>A (p.Arg142Gln)	GJB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21081	NM_000166.6(GJB1):c.187G>A (p.Val63Ile)	GJB1	Pathogenic	criteria provided, multiple submitters, no conflicts
21082	NM_000166.6(GJB1):c.223C>T (p.Arg75Trp)	GJB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21084	NM_000166.6(GJB1):c.43C>T (p.Arg15Trp)	GJB1	Pathogenic	criteria provided, multiple submitters, no conflicts
21086	NM_000166.6(GJB1):c.556G>A (p.Glu186Lys)	GJB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
216038	NM_000166.6(GJB1):c.305A>G (p.Glu102Gly)	GJB1	Pathogenic	criteria provided, multiple submitters, no conflicts
216039	NM_000166.6(GJB1):c.547C>T (p.Arg183Cys)	GJB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217166	NM_000166.6(GJB1):c.-103C>T	GJB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217167	NM_000166.6(GJB1):c.224G>A (p.Arg75Gln)	GJB1	Pathogenic	criteria provided, multiple submitters, no conflicts
234612	NM_000166.6(GJB1):c.556G>T (p.Glu186Ter)	GJB1	Pathogenic	criteria provided, single submitter
245705	NM_000166.6(GJB1):c.541G>A (p.Val181Met)	GJB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
245724	NM_000166.6(GJB1):c.282C>A (p.His94Gln)	GJB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
245946	NM_000166.6(GJB1):c.112G>A (p.Val38Met)	GJB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 106 · Orphanet: 152 · 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
EGR2	Definitive	Autosomal recessive	Charcot-Marie-Tooth disease type 4E	10
FGD4	Definitive	Autosomal recessive	Charcot-Marie-Tooth disease	4
FIG4	Definitive	Autosomal recessive	Charcot-Marie-Tooth disease type 4J	15
MPZ	Definitive	Autosomal dominant	Charcot-Marie-Tooth disease	11
NEFL	Definitive	Autosomal dominant	Charcot-Marie-Tooth disease	9
SORD	Definitive	Autosomal recessive	Charcot-Marie-Tooth disease	8
YARS1	Definitive	Autosomal dominant	Charcot-Marie-Tooth disease	6
DHX9	Strong	Autosomal dominant	Charcot-Marie-Tooth disease	3
DPYSL2	Strong	X-linked	Charcot-Marie-Tooth disease	4
DRP2	Strong	X-linked	Charcot-Marie-Tooth disease	2
GNB4	Strong	Autosomal dominant	Charcot-Marie-Tooth disease dominant intermediate F	4
LITAF	Strong	Autosomal dominant	Charcot-Marie-Tooth disease type 1C	4
MARS1	Strong	Autosomal dominant	Charcot-Marie-Tooth disease axonal type 2U	12
ARPC3	Moderate	Autosomal dominant	Charcot-Marie-Tooth disease
DGAT2	Moderate	Autosomal dominant	Charcot-Marie-Tooth disease	2
SCO2	Moderate	Autosomal recessive	Charcot-Marie-Tooth disease	8
AHNAK2	Limited	Autosomal recessive	Charcot-Marie-Tooth disease	2
CFAP276	Limited	Autosomal dominant	Charcot-Marie-Tooth disease

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
YARS1	Orphanet:100045	Autosomal dominant intermediate Charcot-Marie-Tooth disease type C
LITAF	Orphanet:101083	Charcot-Marie-Tooth disease type 1C
FIG4	Orphanet:139515	Charcot-Marie-Tooth disease type 4J
FIG4	Orphanet:208441	Bilateral parasagittal parieto-occipital polymicrogyria
FIG4	Orphanet:3472	Yunis-Varon syndrome
FIG4	Orphanet:803	Amyotrophic lateral sclerosis
FGD4	Orphanet:99954	Charcot-Marie-Tooth disease type 4H
GNB4	Orphanet:352670	Autosomal dominant intermediate Charcot-Marie-Tooth disease type F
DPYSL2	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
EGR2	Orphanet:101084	Charcot-Marie-Tooth disease type 1D
EGR2	Orphanet:64748	Dejerine-Sottas syndrome
EGR2	Orphanet:99951	Charcot-Marie-Tooth disease type 4E
MARS1	Orphanet:397735	Autosomal dominant Charcot-Marie-Tooth disease type 2U
MARS1	Orphanet:401835	Autosomal recessive spastic paraplegia type 70
MARS1	Orphanet:440427	Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency
MPZ	Orphanet:100046	Autosomal dominant intermediate Charcot-Marie-Tooth disease type D
MPZ	Orphanet:101082	Charcot-Marie-Tooth disease type 1B
MPZ	Orphanet:3115	Roussy-Lévy syndrome
MPZ	Orphanet:324585	Autosomal dominant intermediate Charcot-Marie-Tooth disease with neuropathic pain
MPZ	Orphanet:538574	Palmoplantar keratoderma-hereditary motor and sensory neuropathy syndrome
MPZ	Orphanet:64748	Dejerine-Sottas syndrome
MPZ	Orphanet:99942	Autosomal dominant Charcot-Marie-Tooth disease type 2I
MPZ	Orphanet:99943	Autosomal dominant Charcot-Marie-Tooth disease type 2J
NEFL	Orphanet:101085	Charcot-Marie-Tooth disease type 1F
NEFL	Orphanet:228374	Charcot-Marie-Tooth disease type 2B5
NEFL	Orphanet:99939	Autosomal dominant Charcot-Marie-Tooth disease type 2E
SCO2	Orphanet:1561	Fatal infantile cytochrome C oxidase deficiency
SCO2	Orphanet:521411	Autosomal recessive axonal Charcot-Marie-Tooth disease due to copper metabolism defect
SCO2	Orphanet:98619	Rare isolated myopia
SORD	Orphanet:700508	Distal muscle weakness-foot deformity-elevated sorbitol level-hereditary motor neuropathy
DGAT2	Orphanet:487814	Autosomal dominant Charcot-Marie-Tooth disease type 2 due to DGAT2 mutation
SACS	Orphanet:98	Autosomal recessive spastic ataxia of Charlevoix-Saguenay
SBF1	Orphanet:363981	Charcot-Marie-Tooth disease type 4B3
SCN11A	Orphanet:306577	Hereditary sodium channelopathy-related small fibers neuropathy
SCN11A	Orphanet:391392	Familial episodic pain syndrome with predominantly lower limb involvement
SCN11A	Orphanet:391397	Hereditary sensory and autonomic neuropathy type 7
SCN11A	Orphanet:46348	Paroxysmal extreme pain disorder
SCN11A	Orphanet:88642	Congenital insensitivity to pain-anosmia-neuropathic arthropathy
SCN11A	Orphanet:90026	Primary erythromelalgia
SEMA5A	Orphanet:281	Monosomy 5p syndrome
DST	Orphanet:314381	Hereditary sensory and autonomic neuropathy type 6
DST	Orphanet:412181	Epidermolysis bullosa simplex due to BP230 deficiency
SLC12A6	Orphanet:1496	Corpus callosum agenesis-neuronopathy syndrome
SPG11	Orphanet:2822	Autosomal recessive spastic paraplegia type 11
SPG11	Orphanet:300605	Juvenile amyotrophic lateral sclerosis
SPG11	Orphanet:466775	Autosomal recessive Charcot-Marie-Tooth disease type 2X
ATL1	Orphanet:100984	Autosomal dominant spastic paraplegia type 3
ATL1	Orphanet:36386	Hereditary sensory and autonomic neuropathy type 1
SPTLC1	Orphanet:300605	Juvenile amyotrophic lateral sclerosis
SPTLC1	Orphanet:36386	Hereditary sensory and autonomic neuropathy type 1

Cohort genes → proteins

75 cohort genes, 74 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	75

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
YARS1	HGNC:12840	ENSG00000134684	P54577	Tyrosine–tRNA ligase, cytoplasmic	gencc,clinvar
LITAF	HGNC:16841	ENSG00000189067	Q99732	Lipopolysaccharide-induced tumor necrosis factor-alpha factor	gencc,clinvar
FIG4	HGNC:16873	ENSG00000112367	Q92562	Polyphosphoinositide phosphatase	gencc,clinvar
FGD4	HGNC:19125	ENSG00000139132	Q96M96	FYVE, RhoGEF and PH domain-containing protein 4	gencc,clinvar
GNB4	HGNC:20731	ENSG00000114450	Q9HAV0	Guanine nucleotide-binding protein subunit beta-4	gencc,clinvar
DHX9	HGNC:2750	ENSG00000135829	Q08211	ATP-dependent RNA helicase A	gencc,clinvar
DPYSL2	HGNC:3014	ENSG00000092964	Q16555	Dihydropyrimidinase-related protein 2	gencc,clinvar
DRP2	HGNC:3032	ENSG00000102385	Q13474	Dystrophin-related protein 2	gencc,clinvar
EGR2	HGNC:3239	ENSG00000122877	P11161	E3 SUMO-protein ligase EGR2	gencc,clinvar
MARS1	HGNC:6898	ENSG00000166986	P56192	Methionine–tRNA ligase, cytoplasmic	gencc,clinvar
MPZ	HGNC:7225	ENSG00000158887	P25189	Myelin protein P0	gencc,clinvar
NEFL	HGNC:7739	ENSG00000277586	P07196	Neurofilament light polypeptide	gencc,clinvar
SCO2	HGNC:10604	ENSG00000284194	O43819	Cytochrome c oxidase assembly factor SCO2	gencc
SORD	HGNC:11184	ENSG00000140263	Q00796	Sorbitol dehydrogenase	gencc
DGAT2	HGNC:16940	ENSG00000062282	Q96PD7	Diacylglycerol O-acyltransferase 2	gencc
AHNAK2	HGNC:20125	ENSG00000185567	Q8IVF2	Protein AHNAK2	gencc
CFAP276	HGNC:32331	ENSG00000179902	Q5T5A4	Cilia- and flagella-associated protein 276	gencc
ARPC3	HGNC:706	ENSG00000111229	O15145	Actin-related protein 2/3 complex subunit 3	gencc
SACS	HGNC:10519	ENSG00000151835	Q9NZJ4	Sacsin	clinvar
SBF1	HGNC:10542	ENSG00000100241	O95248	Myotubularin-related protein 5	clinvar
SCN11A	HGNC:10583	ENSG00000168356	Q9UI33	Sodium channel protein type 11 subunit alpha	clinvar
SEMA5A	HGNC:10736	ENSG00000112902	Q13591	Semaphorin-5A	clinvar
DST	HGNC:1090	ENSG00000151914	Q03001	Dystonin	clinvar
SLC12A6	HGNC:10914	ENSG00000140199	Q9UHW9	Solute carrier family 12 member 6	clinvar
SPG11	HGNC:11226	ENSG00000104133	Q96JI7	Spatacsin	clinvar
ATL1	HGNC:11231	ENSG00000198513	Q8WXF7	Atlastin-1	clinvar
SPTLC1	HGNC:11277	ENSG00000090054	O15269	Serine palmitoyltransferase 1	clinvar
SPTLC2	HGNC:11278	ENSG00000100596	O15270	Serine palmitoyltransferase 2	clinvar
SYP	HGNC:11506	ENSG00000102003	P08247	Synaptophysin	clinvar
TFG	HGNC:11758	ENSG00000114354	Q92734	Protein TFG	clinvar
TTR	HGNC:12405	ENSG00000118271	P02766	Transthyretin	clinvar
PRX	HGNC:13797	ENSG00000105227	Q9BXM0	Periaxin	clinvar
CNTNAP2	HGNC:13830	ENSG00000174469	Q9UHC6	Contactin-associated protein-like 2	clinvar
SLC5A7	HGNC:14025	ENSG00000115665	Q9GZV3	High affinity choline transporter 1	clinvar
ARHGEF10	HGNC:14103	ENSG00000104728	O15013	Rho guanine nucleotide exchange factor 10	clinvar
SHANK3	HGNC:14294	ENSG00000251322	Q9BYB0	SH3 and multiple ankyrin repeat domains protein 3	clinvar
WNK1	HGNC:14540	ENSG00000060237	Q9H4A3	Serine/threonine-protein kinase WNK1	clinvar
BSCL2	HGNC:15832	ENSG00000168000	Q96G97	Seipin	clinvar
GDAP1	HGNC:15968	ENSG00000104381	Q8TB36	Ganglioside-induced differentiation-associated protein 1	clinvar
KIF1B	HGNC:16636	ENSG00000054523	O60333	Kinesin-like protein KIF1B	clinvar
PRDX6	HGNC:16753	ENSG00000117592	P30041	Peroxiredoxin-6	clinvar
MFN2	HGNC:16877	ENSG00000116688	O95140	Mitofusin-2	clinvar
PLD3	HGNC:17158	ENSG00000105223	Q8IV08	5’-3’ exonuclease PLD3	clinvar
BICD2	HGNC:17208	ENSG00000185963	Q8TD16	Protein bicaudal D homolog 2	clinvar
TRPV4	HGNC:18083	ENSG00000111199	Q9HBA0	Transient receptor potential cation channel subfamily V member 4	clinvar
AARS1	HGNC:20	ENSG00000090861	P49588	Alanine–tRNA ligase, cytoplasmic	clinvar
SBF2	HGNC:2135	ENSG00000133812	Q86WG5	Myotubularin-related protein 13	clinvar
COL6A2	HGNC:2212	ENSG00000142173	P12110	Collagen alpha-2(VI) chain	clinvar
MYH14	HGNC:23212	ENSG00000105357	Q7Z406	Myosin-14	clinvar
MORC2	HGNC:23573	ENSG00000133422	Q9Y6X9	ATPase MORC2	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).
LITAF	Lipopolysaccharide-induced tumor necrosis factor-alpha factor	Plays a role in endosomal protein trafficking and in targeting proteins for lysosomal degradation.
FIG4	Polyphosphoinositide phosphatase	Dual specificity phosphatase component of the PI(3,5)P2 regulatory complex which regulates both the synthesis and turnover of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2).
FGD4	FYVE, RhoGEF and PH domain-containing protein 4	Activates CDC42, a member of the Ras-like family of Rho- and Rac proteins, by exchanging bound GDP for free GTP.
GNB4	Guanine nucleotide-binding protein subunit beta-4	Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems.
DHX9	ATP-dependent RNA helicase A	Multifunctional ATP-dependent nucleic acid helicase that unwinds DNA and RNA in a 3’ to 5’ direction and that plays important roles in many processes, such as DNA replication, transcriptional activation, post-transcriptional RNA regulation…
DPYSL2	Dihydropyrimidinase-related protein 2	Plays a role in neuronal development and polarity, as well as in axon growth and guidance, neuronal growth cone collapse and cell migration.
DRP2	Dystrophin-related protein 2	Required for normal myelination and for normal organization of the cytoplasm and the formation of Cajal bands in myelinating Schwann cells.
EGR2	E3 SUMO-protein ligase EGR2	Sequence-specific DNA-binding transcription factor.
MARS1	Methionine–tRNA ligase, cytoplasmic	Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA.
MPZ	Myelin protein P0	Is an adhesion molecule necessary for normal myelination in the peripheral nervous system.
NEFL	Neurofilament light polypeptide	Neurofilaments usually contain three intermediate filament proteins: NEFL, NEFM, and NEFH which are involved in the maintenance of neuronal caliber.
SCO2	Cytochrome c oxidase assembly factor SCO2	Copper metallochaperone essential for the synthesis and maturation of cytochrome c oxidase subunit II (MT-CO2/COX2); together with SCO1, facilitates the incorporation of copper into the Cu(A) site of MT-CO2/COX2.
SORD	Sorbitol dehydrogenase	Polyol dehydrogenase that catalyzes the reversible NAD(+)-dependent oxidation of various sugar alcohols.
DGAT2	Diacylglycerol O-acyltransferase 2	Essential acyltransferase that catalyzes the terminal and only committed step in triacylglycerol synthesis by using diacylglycerol and fatty acyl CoA as substrates.
CFAP276	Cilia- and flagella-associated protein 276	Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating.
ARPC3	Actin-related protein 2/3 complex subunit 3	Component of the Arp2/3 complex, a multiprotein complex that mediates actin polymerization upon stimulation by nucleation-promoting factor (NPF).
SACS	Sacsin	Co-chaperone which acts as a regulator of the Hsp70 chaperone machinery and may be involved in the processing of other ataxia-linked proteins.
SBF1	Myotubularin-related protein 5	Acts as an adapter for the phosphatase MTMR2 to regulate MTMR2 catalytic activity and subcellular location.
SCN11A	Sodium channel protein type 11 subunit alpha	Sodium channel mediating the voltage-dependent sodium ion permeability of excitable membranes.
SEMA5A	Semaphorin-5A	Bifunctional axonal guidance cue regulated by sulfated proteoglycans; attractive effects result from interactions with heparan sulfate proteoglycans (HSPGs), while the inhibitory effects depend on interactions with chondroitin sulfate prot…
DST	Dystonin	Cytoskeletal linker protein.
SLC12A6	Solute carrier family 12 member 6	Mediates electroneutral potassium-chloride cotransport when activated by cell swelling.
SPG11	Spatacsin	May play a role in neurite plasticity by maintaining cytoskeleton stability and regulating synaptic vesicle transport.
ATL1	Atlastin-1	Atlastin-1 (ATL1) is a membrane-anchored GTPase that mediates the GTP-dependent fusion of endoplasmic reticulum (ER) membranes, maintaining the continuous ER network.
SPTLC1	Serine palmitoyltransferase 1	Component of the serine palmitoyltransferase multisubunit enzyme (SPT) that catalyzes the initial and rate-limiting step in sphingolipid biosynthesis by condensing L-serine and activated acyl-CoA (most commonly palmitoyl-CoA) to form long-…
SPTLC2	Serine palmitoyltransferase 2	Component of the serine palmitoyltransferase multisubunit enzyme (SPT) that catalyzes the initial and rate-limiting step in sphingolipid biosynthesis by condensing L-serine and activated acyl-CoA (most commonly palmitoyl-CoA) to form long-…
SYP	Synaptophysin	Possibly involved in structural functions as organizing other membrane components or in targeting the vesicles to the plasma membrane.
TFG	Protein TFG	Plays a role in the normal dynamic function of the endoplasmic reticulum (ER) and its associated microtubules.
TTR	Transthyretin	Thyroid hormone-binding protein.
PRX	Periaxin	Scaffolding protein that functions as part of a dystroglycan complex in Schwann cells, and as part of EZR and AHNAK-containing complexes in eye lens fiber cells.
CNTNAP2	Contactin-associated protein-like 2	Required for gap junction formation.
SLC5A7	High affinity choline transporter 1	High-affinity Na(+)-coupled choline transmembrane symporter.
ARHGEF10	Rho guanine nucleotide exchange factor 10	May play a role in developmental myelination of peripheral nerves.
SHANK3	SH3 and multiple ankyrin repeat domains protein 3	Major scaffold postsynaptic density protein which interacts with multiple proteins and complexes to orchestrate the dendritic spine and synapse formation, maturation and maintenance.
WNK1	Serine/threonine-protein kinase WNK1	Serine/threonine-protein kinase component of the WNK1-SPAK/OSR1 kinase cascade, which acts as a key regulator of blood pressure and regulatory volume increase by promoting ion influx.
BSCL2	Seipin	Plays a crucial role in the formation of lipid droplets (LDs) which are storage organelles at the center of lipid and energy homeostasis.
GDAP1	Ganglioside-induced differentiation-associated protein 1	Regulates the mitochondrial network by promoting mitochondrial fission.
KIF1B	Kinesin-like protein KIF1B	Has a plus-end-directed microtubule motor activity and functions as a motor for transport of vesicles and organelles along microtubules.
PRDX6	Peroxiredoxin-6	Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively.
MFN2	Mitofusin-2	Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion.
PLD3	5’-3’ exonuclease PLD3	5’->3’ exonuclease that hydrolyzes the phosphodiester bond of single-stranded DNA (ssDNA) and RNA molecules to form nucleoside 3’-monophosphates and 5’-end 5’-hydroxy deoxyribonucleotide/ribonucleotide fragments.
BICD2	Protein bicaudal D homolog 2	Acts as an adapter protein linking the dynein motor complex to various cargos and converts dynein from a non-processive to a highly processive motor in the presence of dynactin.
TRPV4	Transient receptor potential cation channel subfamily V member 4	Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity.
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).
SBF2	Myotubularin-related protein 13	Guanine nucleotide exchange factor (GEF) which activates RAB21 and possibly RAB28.
COL6A2	Collagen alpha-2(VI) chain	Collagen VI acts as a cell-binding protein.
MYH14	Myosin-14	Cellular myosin that appears to play a role in cytokinesis, cell shape, and specialized functions such as secretion and capping.
MORC2	ATPase MORC2	ATP-dependent chromatin remodeler essential for epigenetic silencing by the HUSH (human silencing hub) complex.
INF2	Inverted formin-2	Severs actin filaments and accelerates their polymerization and depolymerization.

Protein-family classification

Druggable: 18 · Difficult: 17 · Unknown: 40 · Druggable fraction: 0.24

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
Scaffold/PPI	11	2.5×	0.034
Enzyme (other)	11	1.8×	0.207
Ion channel	2	3.0×	0.437
Phosphatase	2	2.2×	0.506
Transporter	1	1.0×	0.937
Other/Unknown	40	1.0×	0.937
Transcription factor	6	0.7×	0.937
Antibody/Immunoglobulin	1	0.4×	0.937
Kinase	1	0.4×	0.937

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
LITAF	Other/Unknown	no		LITAF, LITAF_fam
FIG4	Other/Unknown	no		SAC_dom, Fig4-like
FGD4	Transcription factor	no		DH_dom, Znf_FYVE, PH_domain
GNB4	Scaffold/PPI	no		WD40_G-protein_beta-like, WD40_rpt, WD40/YVTN_repeat-like_dom_sf
DHX9	Enzyme (other)	yes	3.6.4.13	Helicase_C-like, DNA/RNA_helicase_DEAH_CS, Helicase-assoc_dom
DPYSL2	Other/Unknown	no		Amidohydro-rel, Metal-dep_hydrolase_composite, Hydantoinase/dihydroPyrase
DRP2	Transcription factor	no		Znf_ZZ, WW_dom, Spectrin_repeat
EGR2	Transcription factor	no		Znf_C2H2_type, EGR_N, Znf_C2H2_sf
MARS1	Enzyme (other)	yes	6.1.1.10	WHEP-TRS_dom, aa-tRNA-synth_I_CS, GST_C
MPZ	Antibody/Immunoglobulin	yes		Myelin_P0-rel, Ig_sub, Ig-like_dom
NEFL	Other/Unknown	no		Intermed_filament_DNA-bd, IF_conserved, IF_rod_dom
SCO2	Other/Unknown	no		SCO1/SenC, Thioredoxin_domain, Synth_of_cyt-c-oxidase_Sco1/2
SORD	Enzyme (other)	yes	1.1.1.14	ADH_Zn_CS, GroES-like_sf, ADH-like_C
DGAT2	Enzyme (other)	yes	2.3.1.20	DAGAT
AHNAK2	Scaffold/PPI	no		PDZ, PDZ_sf, Myelin_sheath_structural
CFAP276	Other/Unknown	no		CFAP276
ARPC3	Other/Unknown	no		ARPC3, ARPC3_sf
SACS	Other/Unknown	no		Ubiquitin-like_dom, DnaJ_domain, HEPN_dom
SBF1	Phosphatase	yes	3.1.3.16	cDENN_dom, PH_domain, GRAM
SCN11A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_trans_assoc_dom
SEMA5A	Scaffold/PPI	no		TSP1_rpt, Semap_dom, Plexin_repeat
DST	Scaffold/PPI	no		Plectin_repeat, SH3_domain, Actinin_actin-bd_CS
SLC12A6	Other/Unknown	no		KCL_cotranspt, AA-permease/SLC12A_dom, SLC12A_fam
SPG11	Other/Unknown	no		Spatacsin, Spatacsin_C_dom
ATL1	Other/Unknown	no		Guanylate-bd_N, P-loop_NTPase, G_GB1_RHD3_dom
SPTLC1	Enzyme (other)	yes	2.3.1.50	Aminotransferase_I/II_large, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase_small
SPTLC2	Enzyme (other)	yes	2.3.1.50	Aminotrans_II_pyridoxalP_BS, Aminotransferase_I/II_large, PyrdxlP-dep_Trfase_major
SYP	Other/Unknown	no		Synaptophysin/porin, Marvel
TFG	Other/Unknown	no		PB1_dom, TFG, PB1_TFG
TTR	Other/Unknown	no		Transthyretin/HIU_hydrolase, Transthyretin/HIU_hydrolase_d, Thyroxine_BS
PRX	Scaffold/PPI	no		PDZ, PDZ_sf, Myelin_sheath_structural
CNTNAP2	Other/Unknown	no		FA58C, EGF, Laminin_G
SLC5A7	Transporter	yes		Na/solute_symporter, Na/Glc_symporter_sf, Choline_transporter
ARHGEF10	Scaffold/PPI	no		DH_dom, WD40/YVTN_repeat-like_dom_sf, DBL_dom_sf
SHANK3	Scaffold/PPI	no		SH3_domain, PDZ, SAM
WNK1	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
BSCL2	Other/Unknown	no		Seipin
GDAP1	Other/Unknown	no		Glutathione_S-Trfase_N, Glutathione-S-Trfase_C-like, GST_C_GDAP1
KIF1B	Scaffold/PPI	no		FHA_dom, Kinesin_motor_dom, PH_domain
PRDX6	Enzyme (other)	yes	1.11.1.27	AhpC/TSA, Thioredoxin_domain, Peroxiredoxin_C
MFN2	Other/Unknown	no		Fzo/mitofusin_HR2, Mitofusin_fam, P-loop_NTPase
PLD3	Other/Unknown	no		PLipase_D/transphosphatidylase, PLDc_3, Diverse_PLD-related
BICD2	Other/Unknown	no		BICD
TRPV4	Ion channel	yes		Ankyrin_rpt, Ion_trans_dom, TrpV1-4
AARS1	Other/Unknown	no		Ala-tRNA-lgiase_IIc, DHHA1_dom, Transl_B-barrel_sf
SBF2	Phosphatase	yes		cDENN_dom, PH_domain, GRAM
COL6A2	Other/Unknown	no		VWF_A, Collagen, vWFA_dom_sf
MYH14	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail
MORC2	Transcription factor	no		Znf_CW, HATPase_C_sf, Morc_S5

Expression context

Cohort genes with no expression data: 0.

67 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)	75
unknown	0

Top tissues across cohort

Tissue	Cohort genes
secondary oocyte	8
sural nerve	7
calcaneal tendon	6
tibial nerve	5
granulocyte	5
endothelial cell	4
lateral nuclear group of thalamus	4
middle temporal gyrus	4
upper leg skin	4
cortical plate	4
dorsal root ganglion	4
right hemisphere of cerebellum	4
left testis	4
right testis	4
corpus callosum	4
medial globus pallidus	4
oocyte	4
ganglionic eminence	3
ventricular zone	3
inferior vagus X ganglion	3

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
LITAF	294	ubiquitous	marker	blood, palpebral conjunctiva, periodontal ligament
FIG4	295	ubiquitous	marker	middle temporal gyrus, endothelial cell, lateral nuclear group of thalamus
FGD4	252	ubiquitous	marker	jejunal mucosa, calcaneal tendon, ileal mucosa
GNB4	258	ubiquitous	marker	upper arm skin, secondary oocyte, upper leg skin
DHX9	295	ubiquitous	marker	ventricular zone, ganglionic eminence, cortical plate
DPYSL2	301	ubiquitous	marker	inferior vagus X ganglion, subthalamic nucleus, substantia nigra pars compacta
DRP2	151	broad	marker	trigeminal ganglion, tibial nerve, dorsal root ganglion
EGR2	143	ubiquitous	marker	gall bladder, tibial nerve, granulocyte
MARS1	301	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
MPZ	178	ubiquitous	marker	tibial nerve, sural nerve, olfactory bulb
NEFL	214	broad	marker	dorsal root ganglion, pons, lateral nuclear group of thalamus
SCO2	260	ubiquitous	yes	right uterine tube, granulocyte, mucosa of transverse colon
SORD	199	ubiquitous	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
DGAT2	215	ubiquitous	marker	upper arm skin, upper leg skin, right lobe of liver
AHNAK2	254	ubiquitous	marker	tendon of biceps brachii, upper leg skin, gingival epithelium
CFAP276	164	broad	marker	right uterine tube, bronchial epithelial cell, left testis
ARPC3	180	ubiquitous	marker	monocyte, leukocyte, granulocyte
SACS	286	ubiquitous	marker	Brodmann (1909) area 23, middle frontal gyrus, frontal pole
SBF1	278	ubiquitous	yes	left testis, right testis, right lobe of thyroid gland
SCN11A	166	broad	marker	buccal mucosa cell, dorsal root ganglion, male germ line stem cell (sensu Vertebrata) in testis
SEMA5A	262	ubiquitous	marker	metanephric glomerulus, renal glomerulus, stromal cell of endometrium
DST	305	ubiquitous	marker	corpus callosum, calcaneal tendon, medial globus pallidus
SLC12A6	274	ubiquitous	marker	esophagus squamous epithelium, blood, secondary oocyte
SPG11	295	ubiquitous	marker	bronchial epithelial cell, granulocyte, calcaneal tendon
ATL1	241	ubiquitous	marker	middle temporal gyrus, Brodmann (1909) area 23, endothelial cell
SPTLC1	300	ubiquitous	marker	esophagus squamous epithelium, oral cavity, epithelium of esophagus
SPTLC2	274	ubiquitous	marker	corpus callosum, inferior vagus X ganglion, medial globus pallidus
SYP	206	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
TFG	288	ubiquitous	marker	secondary oocyte, jejunal mucosa, gingival epithelium

Protein interactions among cohort

Intra-cohort edges: 85.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNMT1	7,179
DHX9	6,255
MARS1	5,727
YARS1	4,793
DNM2	4,715
NEFL	4,644
TTR	4,528
DYNC1H1	4,215
PRDX6	4,106
HADHB	4,047

Intra-cohort edges

A	B	Sources
AARS1	GARS1	string_interaction
AARS1	HARS1	string_interaction
AARS1	YARS1	string_interaction
ARHGEF10	GJB1	string_interaction
ARHGEF10	HSPB8	intact
ARHGEF10	INF2	intact
ARHGEF10	SBF2	string_interaction
ARHGEF10	SH3TC2	string_interaction
ATL1	DNM2	intact
ATL1	REEP1	string_interaction
ATL1	SPG11	string_interaction
ATL1	YARS1	intact
BICD2	DCTN2	string_interaction
BICD2	DYNC1H1	string_interaction
BICD2	NEFL	biogrid_interaction, intact
BSCL2	GABRG2	biogrid_interaction, intact
BSCL2	GARS1	string_interaction
BSCL2	REEP1	string_interaction
BSCL2	SHANK3	intact
BSCL2	SYP	intact
CTDP1	MED9	intact
DCTN1	DCTN2	biogrid_interaction, intact, string_interaction
DCTN1	DYNC1H1	biogrid_interaction, string_interaction
DCTN1	FIG4	string_interaction
DCTN1	SETX	string_interaction
DCTN2	DYNC1H1	string_interaction
DNMT1	FBXO38	string_interaction
DNMT1	MYH14	biogrid_interaction
DRP2	PRX	biogrid_interaction, string_interaction
EGR2	GJB1	string_interaction
EGR2	PRX	string_interaction
FGD4	FIG4	string_interaction
FGD4	GDAP1	string_interaction
FGD4	GJB1	string_interaction
FGD4	LITAF	string_interaction
FGD4	LRSAM1	string_interaction
FGD4	MORC2	string_interaction
FGD4	NEFL	biogrid_interaction
FGD4	SBF1	string_interaction
FGD4	SBF2	string_interaction
FGD4	SH3TC2	string_interaction
FIG4	LITAF	string_interaction
FIG4	SBF1	string_interaction
FIG4	SBF2	string_interaction
FIG4	SETX	string_interaction
FIG4	SH3TC2	string_interaction
GAN	NEFL	string_interaction
GAN	SACS	string_interaction
GARS1	HARS1	string_interaction
GARS1	MARS1	string_interaction

Structural data

PDB: 57 · AlphaFold-only: 17 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TTR	P02766	462
DYNC1H1	Q14204	97
GABRG2	P18507	75
GLA	P06280	31
DNMT1	P26358	27
TRPV4	Q9HBA0	19
SPTLC1	O15269	17
SPTLC2	O15270	17
DPYSL2	Q16555	15
GJB1	P08034	15
ATL1	Q8WXF7	14
GARS1	P41250	14
DCTN1	Q14203	13
SLC5A7	Q9GZV3	12
MED9	Q9NWA0	11
INF2	Q27J81	10
MED25	Q71SY5	10
HARS1	P12081	10
MORC2	Q9Y6X9	9
YARS1	P54577	8
SLC12A6	Q9UHW9	8
GDAP1	Q8TB36	8
MARS1	P56192	7
SACS	Q9NZJ4	7
PLD3	Q8IV08	7
DHX9	Q08211	6
AARS1	P49588	6
ARPC3	O15145	5
WNK1	Q9H4A3	5
SEMA5A	Q13591	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GNB4	Q9HAV0	97.14
DGAT2	Q96PD7	88.52
SH3TC2	Q8TF17	78.63
LRSAM1	Q6UWE0	78.47
SYP	P08247	77.92
SBF1	O95248	74.72
DRP2	Q13474	74.10
SBF2	Q86WG5	73.74
NEFL	P07196	73.66
FGD4	Q96M96	70.85
LITAF	Q99732	70.60
SCN11A	Q9UI33	69.66
FBXO38	Q6PIJ6	67.97
REEP1	Q9H902	67.91
ARHGEF10	O15013	65.56
SETX	Q7Z333	52.93
EGR2	P11161	49.02

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 456. Enrichment computed across 107 evidence-associated genes (83 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 83 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
EGR2 and SOX10-mediated initiation of Schwann cell myelination	7	31.1×	9e-07	DRP2, EGR2, MPZ, PRX, GJB1, LAMA2, PMP22
Cytosolic tRNA aminoacylation	6	31.8×	6e-06	YARS1, MARS1, AARS1, GARS1, HARS1, KARS1
MHC class II antigen presentation	7	7.5×	0.006	DCTN1, DCTN2, DYNC1H1, DNM2, KIF5A, ARF1, RAB7A
TRKA activation by NGF	2	137.6×	0.006	NGF, NTRK1
PI Metabolism	4	17.2×	0.007	SBF1, SBF2, ARF1, MTMR2
PLC-gamma1 signalling	2	91.7×	0.009	NGF, NTRK1
Signalling to STAT3	2	91.7×	0.009	NGF, NTRK1
Retrograde neurotrophin signalling	3	29.5×	0.009	DNM2, NGF, NTRK1
tRNA Aminoacylation	4	13.8×	0.010	YARS1, MARS1, AARS1, KARS1
Metabolism of lipids	10	3.8×	0.013	SBF1, SPTLC1, SPTLC2, SBF2, MORC2, MED9, MED25, GLA (+2 more)
Synthesis of PIPs at the ER membrane	2	55.0×	0.020	SBF1, MTMR2
Signalling to p38 via RIT and RIN	2	55.0×	0.020	NGF, NTRK1
COPI-independent Golgi-to-ER retrograde traffic	4	10.0×	0.023	BICD2, DCTN1, DCTN2, DYNC1H1
Phospholipid metabolism	4	9.7×	0.025	SBF1, SBF2, ARF1, MTMR2
ARMS-mediated activation	2	39.3×	0.033	NGF, NTRK1
PI3K/AKT activation	2	30.6×	0.049	NGF, NTRK1
Membrane Trafficking	8	3.6×	0.049	SBF1, TFG, KIF1B, BICD2, SBF2, KIF5A, ARF1, ARPC3
Vesicle-mediated transport	8	3.4×	0.065	SBF1, TFG, KIF1B, BICD2, SBF2, KIF5A, ARF1, ARPC3
Synthesis of PIPs at the late endosome membrane	2	22.9×	0.075	FIG4, MTMR2
Frs2-mediated activation	2	22.9×	0.075	NGF, NTRK1
Golgi-to-ER retrograde transport	4	6.4×	0.076	KIF1B, BICD2, KIF5A, ARF1
Metabolism	15	2.1×	0.092	MARS1, SBF1, SCO2, SPTLC1, SPTLC2, SBF2, MORC2, MED9 (+7 more)
MPS IIIB - Sanfilippo syndrome B	1	137.6×	0.109	NAGLU
Defective SLC12A6 causes agenesis of the corpus callosum, with peripheral neuropathy (ACCPN)	1	137.6×	0.109	SLC12A6
Defective SLC5A7 in the neurotransmitter release cycle causes distal hereditary motor neuronopathy 7A (HMN7A)	1	137.6×	0.109	SLC5A7
Defective transport by SLC5A7 causes distal hereditary motor neuronopathy 7A (HMN7A)	1	137.6×	0.109	SLC5A7
Synthesis of PIPs at the early endosome membrane	2	17.2×	0.109	FIG4, MTMR2
Signalling to RAS	2	16.2×	0.109	NGF, NTRK1
Synthesis of PIPs at the Golgi membrane	2	15.3×	0.109	FIG4, ARF1
Synthesis of PIPs at the plasma membrane	3	7.6×	0.109	SBF2, ARF1, MTMR2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 101 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
tRNA aminoacylation for protein translation	4	33.4×	0.005	MARS1, AARS1, GARS1, HARS1
sphinganine biosynthetic process	2	166.8×	0.007	SPTLC1, SPTLC2
myelin assembly	3	55.6×	0.007	FIG4, MTMR2, PMP22
retrograde axonal transport	3	45.5×	0.007	NEFL, DST, DYNC1H1
peripheral nervous system myelin maintenance	3	45.5×	0.007	PRX, SH3TC2, NDRG1
adult behavior	4	18.5×	0.010	CNTNAP2, SHANK3, GABRG2, NAGLU
diadenosine tetraphosphate biosynthetic process	2	111.2×	0.011	GARS1, KARS1
behavioral response to formalin induced pain	2	111.2×	0.011	SCN11A, NTRK1
cellular hypotonic salinity response	2	111.2×	0.011	SLC12A6, TRPV4
intracellular copper ion homeostasis	3	27.8×	0.014	SCO2, ARF1, ATP7A
sensory perception of pain	4	14.8×	0.014	SCN11A, RETREG1, MME, NGF
vocalization behavior	3	26.3×	0.015	CNTNAP2, SHANK3, MYH14
synaptic vesicle transport	3	25.0×	0.015	SPG11, DNM2, KIF5A
neuron apoptotic process	5	9.2×	0.015	AARS1, COL6A2, NGF, NTRK1, ATP7A
positive regulation of lipophagy	2	66.7×	0.019	SPTLC1, SPTLC2
retrograde neuronal dense core vesicle transport	2	66.7×	0.019	KIF1B, KIF5A
nuclear migration	3	21.8×	0.019	DCTN1, DYNC1H1, LMNA
neuron projection morphogenesis	4	10.9×	0.025	CNTNAP2, DNM2, NGF, ATP7A
cell volume homeostasis	3	17.9×	0.030	SLC12A6, WNK1, TRPV4
peripheral nervous system development	3	17.3×	0.030	EGR2, NGF, PMP22
neuron development	4	10.1×	0.030	FIG4, WNK1, MTMR2, NTRK1
Schwann cell differentiation	2	47.7×	0.030	EGR2, LAMA2
motor behavior	3	16.7×	0.030	SPG11, DCTN1, NAGLU
circadian rhythm	4	9.7×	0.030	SCN11A, SETX, NGF, NTRK1
positive regulation of neuron projection development	5	6.8×	0.032	FIG4, FBXO38, SETX, NGF, NTRK1
vocal learning	2	41.7×	0.034	CNTNAP2, SHANK3
anterograde axonal protein transport	2	41.7×	0.034	HSPB1, KIF5A
axon extension	3	14.7×	0.037	SEMA5A, SPG11, NGF
negative regulation of myelination	2	37.1×	0.040	FIG4, MTMR2
neuron cellular homeostasis	3	13.5×	0.044	DCTN1, DNAJB2, ATP7A

Therapeutics

Drugs indicated or in trials for this disease

No drug has an approved disease-direct ChEMBL indication for this disease.

6 drugs in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Baclofen	Phase 3
Sorbitol	Phase 3
Ascorbic Acid	Phase 2
Epalrestat	Phase 2
Mexiletine	Phase 2
Ulipristal Acetate	Phase 2

Drug target analysis

Approved (phase 4): 9 · Phase ≥3: 12 · Phased (≥1): 13 · Undrugged: 62

Druggability breadth: 59 of 107 evidence-associated genes (55%) 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
SORD	EPALRESTAT
DGAT2	OBETICHOLIC ACID
SCN11A	IMIPRAMINE
TTR	TRICLABENDAZOLE
MYH14	TUCATINIB
DNMT1	DECITABINE
GABRG2	ENZALUTAMIDE
GLA	CLOTRIMAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GLA	62	4
GABRG2	55	4
TTR	29	4
SCN11A	15	4
TRPV4	6	3
DNMT1	6	4
DGAT2	3	4
YARS1	2	4
SORD	2	4
SLC5A7	1	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CAPSAICIN	4	YARS1
EPALRESTAT	4	SORD
OBETICHOLIC ACID	4	DGAT2
IMIPRAMINE	4	SCN11A
SERTINDOLE	4	SCN11A
PIMOZIDE	4	SCN11A
NIFEDIPINE	4	SCN11A
DILTIAZEM	4	SCN11A
MIBEFRADIL	4	SCN11A
HALOPERIDOL	4	SCN11A
MEXILETINE	4	SCN11A
AMITRIPTYLINE	4	SCN11A
AMIODARONE	4	SCN11A
CHLORPROMAZINE	4	SCN11A
TRICLABENDAZOLE	4	TTR
AMLEXANOX	4	TTR
TOLCAPONE	4	TTR
DICLOFENAC	4	TTR
LEVOTHYROXINE	4	TTR
TAFAMIDIS	4	TTR
BENZIODARONE	4	TTR
BITHIONOL	4	TTR
BENZBROMARONE	4	TTR
ACORAMIDIS	4	TTR
GEMFIBROZIL	4	TTR
MECLOFENAMIC ACID	4	TTR
DASATINIB	4	TTR
DEXTROTHYROXINE	4	TTR
TRICLOSAN	4	TTR
DIFLUNISAL	4	TTR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 14.

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

Symbol	Assays	Type breakdown
GABRG2	1,155	Binding:940, Functional:201, ADMET:10, Toxicity:4
TTR	423	Binding:391, Functional:32
DNMT1	233	Binding:229, Functional:3, ADMET:1
WNK1	165	Binding:165
GLA	114	Binding:104, Functional:10
TRPV4	99	Binding:94, Functional:5
DGAT2	61	Binding:60, ADMET:1
SLC5A7	34	Binding:24, Functional:10
SCN11A	33	Functional:16, Binding:15, ADMET:2
MARS1	26	Binding:26
SORD	17	Binding:16, Functional:1
YARS1	16	Binding:16
PRDX6	15	Binding:15
DNM2	15	Binding:15
PLD3	13	Binding:13
DHX9	10	Binding:10
GARS1	8	Binding:8
DYNC1H1	7	Binding:7
HARS1	5	Binding:5
SPTLC1	4	Binding:4
SPTLC2	4	Binding:4
DPYSL2	3	Binding:3
MFN2	3	Binding:3
MED25	3	Binding:3
TFG	2	Binding:2
AARS1	2	Binding:2
HADHB	2	Binding:2
LITAF	1	Binding:1
SCO2	1	Binding:1
ARPC3	1	Binding:1
SPG11	1	Binding:1
KIF1B	1	Binding:1
MYH14	1	Binding:1
INF2	1	Binding:1
DCTN1	1	Binding:1
GJB1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
YARS1	6.1.1.1	tyrosine-tRNA ligase
DHX9	3.6.4.13	RNA helicase
MARS1	6.1.1.10	methionine-tRNA ligase
SORD	1.1.1.14	L-iditol 2-dehydrogenase
DGAT2	2.3.1.20	diacylglycerol O-acyltransferase
SBF1	3.1.3.16	protein-serine/threonine phosphatase
SPTLC1	2.3.1.50	serine C-palmitoyltransferase
SPTLC2	2.3.1.50	serine C-palmitoyltransferase
PRDX6	1.11.1.27, 2.3.1.23, 3.1.1.4	glutathione-dependent peroxiredoxin, 1-acylglycerophosphocholine O-acyltransferase, phospholipase A2
DNM2	3.6.5.5	dynamin GTPase
DNMT1	2.1.1.37	DNA (cytosine-5-)-methyltransferase
GARS1	6.1.1.14	glycine-tRNA ligase
GLA	3.2.1.22	alpha-galactosidase
HARS1	6.1.1.21	histidine-tRNA ligase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
TTR	423
WNK1	165
DNMT1	233
GABRG2	1,155
GLA	114

Pharmacogenomics

Cohort genes with a PharmGKB record: 74; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

28 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
OBETICHOLIC ACID	4	DGAT2
IMIPRAMINE	4	SCN11A
SERTINDOLE	4	SCN11A
PIMOZIDE	4	SCN11A
NIFEDIPINE	4	SCN11A
DILTIAZEM	4	SCN11A
MIBEFRADIL	4	SCN11A
HALOPERIDOL	4	SCN11A
AMITRIPTYLINE	4	SCN11A
AMIODARONE	4	SCN11A
CHLORPROMAZINE	4	SCN11A
TRICLABENDAZOLE	4	TTR
AMLEXANOX	4	TTR
TOLCAPONE	4	TTR
DICLOFENAC	4	TTR
LEVOTHYROXINE	4	TTR
TAFAMIDIS	4	TTR
BENZIODARONE	4	TTR
BITHIONOL	4	TTR
BENZBROMARONE	4	TTR
ACORAMIDIS	4	TTR
GEMFIBROZIL	4	TTR
MECLOFENAMIC ACID	4	TTR
DASATINIB	4	TTR
DEXTROTHYROXINE	4	TTR
TRICLOSAN	4	TTR
DIFLUNISAL	4	TTR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	9	YARS1, SORD, DGAT2, SCN11A, TTR, MYH14, DNMT1, GABRG2, GLA
B	Phased (≥1) drug, not yet approved	4	SLC5A7, TRPV4, DYNC1H1, GARS1
C	Druggable family + PDB, no drug	8	DHX9, MARS1, MPZ, SPTLC1, SPTLC2, WNK1, PRDX6, HARS1
D	Druggable family + AlphaFold only, no drug	2	SBF1, SBF2
E	Difficult family or no structure, no drug	52	LITAF, FIG4, FGD4, GNB4, DPYSL2, DRP2, EGR2, NEFL, SCO2, AHNAK2 (+42 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
AARS1	2	YARS1
HARS1	5	GARS1, YARS1
WNK1	165	—
LITAF	1	—
FIG4	0	—
FGD4	0	—
GNB4	0	—
DHX9	10	—
DPYSL2	3	—
DRP2	0	—
EGR2	0	—
MARS1	26	—
MPZ	0	—
NEFL	0	—
SCO2	1	—
AHNAK2	0	—
CFAP276	0	—
ARPC3	1	—
SACS	0	—
SBF1	0	—
SEMA5A	0	—
DST	0	—
SLC12A6	0	—
SPG11	1	—
ATL1	0	—
SPTLC1	4	—
SPTLC2	4	—
SYP	0	—
TFG	2	—
PRX	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 59.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	45
PHASE2	9
PHASE1/PHASE2	3
PHASE2/PHASE3	1
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01289704	PHASE2/PHASE3	UNKNOWN	Treadmill, Stretching and Proprioceptive Exercise (TreSPE) Rehabilitation Program for Charcot-Marie-Tooth Neuropathy Type 1A (CMT1A)
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT07223632	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Treatment of Charcot-Marie-Tooth Disease, Axonal, Type 2S (CMT2S) in an Individual Patient
NCT00271635	PHASE2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT00541164	PHASE1/PHASE2	COMPLETED	Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT02561702	PHASE2	COMPLETED	Mexiletine for Muscle Cramps in Charcot Marie Tooth Disease
NCT02967679	PHASE2	COMPLETED	SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
NCT03124459	PHASE2	TERMINATED	Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
NCT03254199	PHASE2	TERMINATED	A Study to Assess the Safety and Effectiveness of FLX-787 in Subjects With Charcot-Marie-Tooth Disease Experiencing Muscle Cramps.
NCT03943290	PHASE2	TERMINATED	Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
NCT05361031	PHASE1/PHASE2	COMPLETED	The Safety and Tolerability of Engensis (VM202) in Patients With Charcot-Marie-Tooth Disease Subtype 1A (CMT1A)
NCT05777226	PHASE2	UNKNOWN	Research of SORD-CMT Natural History and Epalrestat Treatment
NCT06482437	PHASE2	COMPLETED	Safety and Efficacy of NMD670 in Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease
NCT01193075	Not specified	RECRUITING	Natural History Evaluation of Charcot Marie Tooth Disease (CMT) Types CMT1B, CMT2A, CMT4A, CMT4C, and Others
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT04010188	Not specified	RECRUITING	A Registered Cohort Study on Charcot-Marie-Tooth Disease
NCT05011006	Not specified	NOT_YET_RECRUITING	NT-3 Levels and Function in Individuals With CMT
NCT05902351	Not specified	RECRUITING	Natural History Study for Charcot Marie Tooth Disease
NCT06203093	Not specified	RECRUITING	Charcot-Marie-Tooth Disease (CMT) Biological Sample Collection for IPSC Generation and Biobanking
NCT06666816	Not specified	RECRUITING	Observational Study to Observe Variations of Gait Parameters in Patients With Neuromuscular Diseases
NCT06708468	Not specified	RECRUITING	Personalized Training for People With Rare Neuromuscular Disorders
NCT06794489	Not specified	RECRUITING	Longitudinal Biomarkers With Selected Outcome Measures In CMT
NCT06881979	Not specified	RECRUITING	High-Tech Rehabilitation Pathway for Chronic Adult Neuromuscular Diseases - Fit4MedRob-Chronic MND Project
NCT07038239	Not specified	RECRUITING	Genotype/Phenotype Correlation of MORC2 Mutations
NCT07072676	Not specified	ENROLLING_BY_INVITATION	The Use of Assistive Gait Devices Can Reduce the Risk of Falls in Patients With Neuromuscular Diseases Following a Training Period.
NCT07136844	Not specified	RECRUITING	Gait Analysis Parameter and Upper Limb Evaluation in Adult Patients With Neurological or Metabolic Pathology
NCT07152197	Not specified	RECRUITING	Effects of Resistance Exercises in Hereditary Sensory-Motor Neuropathy (Charcot-Marie-Tooth Disease)
NCT07188415	Not specified	RECRUITING	CMT Gait, Mobility, Balance - AOFAS Grant
NCT07432035	Not specified	NOT_YET_RECRUITING	Walking Function Outcomes Following Surgical Correction With Rehabilitation Versus Physical Therapy Alone in Charcot-Marie-Tooth Disease: A Bidirectional Cohort Study
NCT07476365	Not specified	RECRUITING	A Multi-omic Approach to the Identification of Novel Biomarkers in Early Charcot-Marie-Tooth 1A Disease (CMT1A)
NCT07478172	Not specified	RECRUITING	Effects of Whole-body Electrical Muscle Stimulation Exercise on Adults With Neuromuscular Disease
NCT07570446	Not specified	RECRUITING	AUTONOMOUS DISORDERS IN CMT
NCT07570459	Not specified	RECRUITING	TREMOR IN CHARCOT-MARIE-TOOTH
NCT00149045	Not specified	COMPLETED	Follow up and Observation of Charcot Marie Tooth Disease in Families
NCT01203085	Not specified	COMPLETED	Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale for Children With CMT
NCT01455623	Not specified	COMPLETED	Development and Validation of a Disability Severity Index for CMT
NCT01918826	Not specified	UNKNOWN	Evaluation of the Analgesic Efficiency of the Transcutaneous Neurostimulation in the Charcot Syndrome Marie Tooth on the Pains of Lower Limbs
NCT02001038	Not specified	COMPLETED	Survey of Current Management of Orthopaedic Complications in CMT Patients
NCT02011204	Not specified	COMPLETED	Study of Electrical Impedance Myography (EIM) in ALS

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
EPALRESTAT	4	1
MEXILETINE	4	1
SORBITOL	4	1
UBIDECARENONE	3	1
EFMITERMANT ALFA	2	2
CHEMBL3976215	0	1