Charcot-Marie-Tooth disease type 2

Summary

Charcot-Marie-Tooth disease type 2 (MONDO:0018993) is a disease (an umbrella term covering 38 Mondo subtypes) caused by variants in NEFL and RAB7A, with 30 cohort genes and 1 clinical trial.

At a glance

• Prevalence: 1-5 / 10 000 (Europe)
• Causal genes: NEFL (GenCC Definitive), RAB7A (GenCC Definitive)
• Umbrella term: 38 Mondo subtypes
• Cohort genes: 30
• ClinVar variants: 7,509
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000		Europe	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease type 2
Mondo ID	MONDO:0018993
Orphanet	64746
DOID	DOID:0050539
ICD-11	403896648
SNOMED CT	715665006
UMLS	C0270914
MedGen	124378
GARD	0012431
Is cancer (heuristic)	no

Also known as: autosomal dominant axonal Charcot-Marie-Tooth disease · Charcot-Marie-Tooth type 2 · CMT2 · hereditary motor and sensory neuropathy type 2

Data availability: 7,509 ClinVar variants · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 38 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 › Charcot-Marie-Tooth disease type 2

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 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

Subtypes (38): Charcot-Marie-Tooth disease type 2A1, Charcot-Marie-Tooth disease type 2B, Charcot-Marie-Tooth disease type 2D, Charcot-Marie-Tooth disease type 2B1, Charcot-Marie-Tooth disease type 2B2, Charcot-Marie-Tooth disease axonal type 2C, Charcot-Marie-Tooth disease axonal type 2F, Charcot-Marie-Tooth disease type 2I, Charcot-Marie-Tooth disease type 2E, Charcot-Marie-Tooth disease axonal type 2H, Charcot-Marie-Tooth disease type 2J, Charcot-Marie-Tooth disease axonal type 2K, Charcot-Marie-Tooth disease axonal type 2L, Charcot-Marie-Tooth disease type 2A2, giant axonal neuropathy 2, Charcot-Marie-Tooth disease axonal type 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

600 retrieved; paginated sample, class counts are floors:

264 likely benign, 254 uncertain significance, 31 conflicting classifications of pathogenicity, 23 pathogenic, 11 likely pathogenic, 8 benign, 6 benign/likely benign, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1037702	NM_001605.3(AARS1):c.651del (p.Val218fs)	AARS1	Pathogenic	criteria provided, single submitter
1076721	NM_001122955.4(BSCL2):c.1113del (p.Thr372fs)	BSCL2	Pathogenic	criteria provided, single submitter
1010089	NM_170707.4(LMNA):c.239_256del (p.Ala80_Leu85del)	LMNA	Pathogenic	criteria provided, single submitter
1068933	NM_170707.4(LMNA):c.1253del (p.Lys418fs)	LMNA	Pathogenic	criteria provided, single submitter
1069289	NM_170707.4(LMNA):c.481G>T (p.Glu161Ter)	LMNA	Pathogenic	criteria provided, single submitter
1069324	NM_170707.4(LMNA):c.1150G>A (p.Glu384Lys)	LMNA	Pathogenic	criteria provided, single submitter
1069623	NM_170707.4(LMNA):c.526del (p.Ala175_Leu176insTer)	LMNA	Pathogenic	criteria provided, single submitter
1069958	NM_170707.4(LMNA):c.1232del (p.Gly411fs)	LMNA	Pathogenic	criteria provided, single submitter
1070600	NM_170707.4(LMNA):c.298_299del (p.Ala100fs)	LMNA	Pathogenic	criteria provided, multiple submitters, no conflicts
1071831	NM_170707.4(LMNA):c.792_793insGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGATGCGGGCGGATCACGAGGTCAGGAGATCGAGACCATCCCGGCTAAAACGGTGAAACCCCGTCTCTACNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAGAAGGAGCTGGAG (p.Lys265delinsAlaGlyArgGlyGlySerArgLeuTer)	LMNA	Pathogenic	criteria provided, single submitter
1071868	NC_000001.10:g.(?156083461)(156110880_?)del	LMNA	Pathogenic	criteria provided, single submitter
1071869	NC_000001.10:g.(?156084700)(156108907_?)del	LMNA	Pathogenic	criteria provided, single submitter
1071935	NM_170707.4(LMNA):c.275T>C (p.Leu92Pro)	LMNA	Pathogenic	criteria provided, single submitter
1072048	NM_170707.4(LMNA):c.1526del (p.Pro509fs)	LMNA	Pathogenic	criteria provided, single submitter
1072148	NM_170707.4(LMNA):c.186dup (p.Ile63fs)	LMNA	Pathogenic	criteria provided, single submitter
1072780	NM_170707.4(LMNA):c.1377dup (p.Glu460Ter)	LMNA	Pathogenic	criteria provided, single submitter
1073872	NM_170707.4(LMNA):c.1321del (p.Ala441fs)	LMNA	Pathogenic	criteria provided, multiple submitters, no conflicts
1074127	NM_170707.4(LMNA):c.194A>G (p.Glu65Gly)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075208	NM_170707.4(LMNA):c.1608+2T>G	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076432	NM_170707.4(LMNA):c.1248del (p.Lys418fs)	LMNA	Pathogenic	criteria provided, single submitter
1076448	NM_170707.4(LMNA):c.1414C>T (p.Gln472Ter)	LMNA	Pathogenic	criteria provided, single submitter
1076704	NM_170707.4(LMNA):c.1A>T (p.Met1Leu)	LMNA	Pathogenic	criteria provided, single submitter
1066607	NM_014874.4(MFN2):c.828G>T (p.Gln276His)	MFN2	Pathogenic	criteria provided, single submitter
1073982	NM_014874.4(MFN2):c.2054_2069+1171del	MFN2	Pathogenic	criteria provided, single submitter
1076044	NC_000001.10:g.(?12058817)(12059162_?)del	MFN2	Pathogenic	criteria provided, single submitter
1193107	NM_014874.4(MFN2):c.382C>T (p.His128Tyr)	MFN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067828	NM_001122955.4(BSCL2):c.1006-1G>A	BSCL2	Likely pathogenic	criteria provided, single submitter
1299492	NM_004984.4(KIF5A):c.2987A>G (p.Asp996Gly)	KIF5A	Likely pathogenic	criteria provided, single submitter
1025696	NM_170707.4(LMNA):c.869A>T (p.Glu290Val)	LMNA	Likely pathogenic	criteria provided, single submitter
1063701	NM_170707.4(LMNA):c.1040A>C (p.Glu347Ala)	LMNA	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 70 · 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
NEFL	Definitive	Autosomal dominant	Charcot-Marie-Tooth disease	9
RAB7A	Definitive	Autosomal dominant	Charcot-Marie-Tooth disease type 2	4
MYO9B	Moderate	Autosomal recessive	Charcot-Marie-Tooth disease type 2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
RAB7A	Orphanet:99936	Autosomal dominant Charcot-Marie-Tooth disease type 2B
SLC5A7	Orphanet:139589	Distal hereditary motor neuropathy type 7
SLC5A7	Orphanet:98914	Presynaptic congenital myasthenic syndromes
BSCL2	Orphanet:100998	Autosomal dominant spastic paraplegia type 17
BSCL2	Orphanet:139536	Distal hereditary motor neuropathy type 5
BSCL2	Orphanet:363400	Progressive encephalopathy-severe neurodegeneration-lipodystrophy syndrome
BSCL2	Orphanet:696289	Congenital generalized lipodystrophy type 2
KIF1B	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
KIF1B	Orphanet:99946	Autosomal dominant Charcot-Marie-Tooth disease type 2A1
MFN2	Orphanet:2398	Multiple symmetric lipomatosis
MFN2	Orphanet:64751	Hereditary motor and sensory neuropathy type 5
MFN2	Orphanet:90118	Severe early-onset axonal neuropathy due to MFN2 deficiency
MFN2	Orphanet:90120	Hereditary motor and sensory neuropathy type 6
MFN2	Orphanet:99947	Autosomal dominant Charcot-Marie-Tooth disease type 2A2
AARS1	Orphanet:228174	Autosomal dominant Charcot-Marie-Tooth disease type 2N
AARS1	Orphanet:33364	Trichothiodystrophy
AARS1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
COL12A1	Orphanet:536516	Myopathic Ehlers-Danlos syndrome
COL12A1	Orphanet:610	Bethlem muscular dystrophy
COL12A1	Orphanet:75840	Ullrich congenital muscular dystrophy
DCTN1	Orphanet:139589	Distal hereditary motor neuropathy type 7
DCTN1	Orphanet:178509	Perry syndrome
DCTN1	Orphanet:803	Amyotrophic lateral sclerosis
MED25	Orphanet:464738	Basel-Vanagaite-Smirin-Yosef syndrome
MED25	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
EMD	Orphanet:98863	X-linked Emery-Dreifuss muscular dystrophy
GARS1	Orphanet:139536	Distal hereditary motor neuropathy type 5
GARS1	Orphanet:99938	Autosomal dominant Charcot-Marie-Tooth disease type 2D
SETX	Orphanet:357043	Amyotrophic lateral sclerosis type 4
SETX	Orphanet:64753	Spinocerebellar ataxia with axonal neuropathy type 2
DNAJB2	Orphanet:314485	Young adult-onset distal hereditary motor neuropathy
DNAJB2	Orphanet:443950	DNAJB2-related Charcot-Marie-Tooth disease type 2
HSPB3	Orphanet:139525	Distal hereditary motor neuropathy type 2
KIF5A	Orphanet:100991	Autosomal dominant spastic paraplegia type 10
KIF5A	Orphanet:324611	Autosomal dominant Charcot-Marie-Tooth disease type 2 due to KIF5A mutation
LMNA	Orphanet:154	Familial isolated dilated cardiomyopathy
LMNA	Orphanet:157973	Congenital muscular dystrophy due to LMNA mutation
LMNA	Orphanet:1662	Restrictive dermopathy
LMNA	Orphanet:168796	Heart-hand syndrome, Slovenian type
LMNA	Orphanet:2229	Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome
LMNA	Orphanet:2348	Familial partial lipodystrophy, Dunnigan type
LMNA	Orphanet:280365	Autosomal semi-dominant severe lipodystrophic laminopathy
LMNA	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
LMNA	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
LMNA	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
LMNA	Orphanet:300751	Familial dilated cardiomyopathy with conduction defect due to LMNA mutation
LMNA	Orphanet:363618	LMNA-related cardiocutaneous progeria syndrome

Cohort genes → proteins

30 cohort genes, 28 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	30

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MYO9B	HGNC:7609	ENSG00000099331	Q13459	Unconventional myosin-IXb	gencc
NEFL	HGNC:7739	ENSG00000277586	P07196	Neurofilament light polypeptide	gencc
RAB7A	HGNC:9788	ENSG00000075785	P51149	Ras-related protein Rab-7a	gencc
SH2D2A	HGNC:10821	ENSG00000027869	Q9NP31	SH2 domain-containing protein 2A	clinvar
SLC5A7	HGNC:14025	ENSG00000115665	Q9GZV3	High affinity choline transporter 1	clinvar
BSCL2	HGNC:15832	ENSG00000168000	Q96G97	Seipin	clinvar
KIF1B	HGNC:16636	ENSG00000054523	O60333	Kinesin-like protein KIF1B	clinvar
MFN2	HGNC:16877	ENSG00000116688	O95140	Mitofusin-2	clinvar
AARS1	HGNC:20	ENSG00000090861	P49588	Alanine–tRNA ligase, cytoplasmic	clinvar
COL12A1	HGNC:2188	ENSG00000111799	Q99715	Collagen alpha-1(XII) chain	clinvar
MED9	HGNC:25487	ENSG00000141026	Q9NWA0	Mediator of RNA polymerase II transcription subunit 9	clinvar
DCTN1	HGNC:2711	ENSG00000204843	Q14203	Dynactin subunit 1	clinvar
KIAA2013	HGNC:28513	ENSG00000116685	Q8IYS2	Uncharacterized protein KIAA2013	clinvar
MED25	HGNC:28845	ENSG00000104973	Q71SY5	Mediator of RNA polymerase II transcription subunit 25	clinvar
RBP7	HGNC:30316	ENSG00000162444	Q96R05	Retinoid-binding protein 7	clinvar
EMD	HGNC:3331	ENSG00000102119	P50402	Emerin	clinvar
MEX3A	HGNC:33482	ENSG00000254726	A1L020	RNA-binding protein MEX3A	clinvar
GARS1	HGNC:4162	ENSG00000106105	P41250	Glycine–tRNA ligase	clinvar
SETX	HGNC:445	ENSG00000107290	Q7Z333	Helicase senataxin	clinvar
HNRNPUL2-BSCL2	HGNC:49189	ENSG00000234857		HNRNPUL2-BSCL2 readthrough (NMD candidate)	clinvar
MIR6800	HGNC:50042	ENSG00000284114		microRNA 6800	clinvar
DNAJB2	HGNC:5228	ENSG00000135924	P25686	DnaJ homolog subfamily B member 2	clinvar
HSPB3	HGNC:5248	ENSG00000169271	Q12988	Heat shock protein beta-3	clinvar
KIF5A	HGNC:6323	ENSG00000155980	Q12840	Kinesin heavy chain isoform 5A	clinvar
AQP1	HGNC:633	ENSG00000240583	P29972	Aquaporin-1	clinvar
LMNA	HGNC:6636	ENSG00000160789	P02545	Prelamin-A/C	clinvar
MME	HGNC:7154	ENSG00000196549	P08473	Neprilysin	clinvar
ATP7A	HGNC:869	ENSG00000165240	Q04656	Copper-transporting ATPase 1	clinvar
KIF1A	HGNC:888	ENSG00000130294	Q12756	Kinesin-like protein KIF1A	clinvar
PMF1	HGNC:9112	ENSG00000160783	Q6P1K2	Polyamine-modulated factor 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MYO9B	Unconventional myosin-IXb	Myosins are actin-based motor molecules with ATPase activity.
NEFL	Neurofilament light polypeptide	Neurofilaments usually contain three intermediate filament proteins: NEFL, NEFM, and NEFH which are involved in the maintenance of neuronal caliber.
RAB7A	Ras-related protein Rab-7a	The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes.
SH2D2A	SH2 domain-containing protein 2A	Could be a T-cell-specific adapter protein involved in the control of T-cell activation.
SLC5A7	High affinity choline transporter 1	High-affinity Na(+)-coupled choline transmembrane symporter.
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.
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.
MFN2	Mitofusin-2	Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion.
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).
COL12A1	Collagen alpha-1(XII) chain	Type XII collagen interacts with type I collagen-containing fibrils, the COL1 domain could be associated with the surface of the fibrils, and the COL2 and NC3 domains may be localized in the perifibrillar matrix.
MED9	Mediator of RNA polymerase II transcription subunit 9	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
DCTN1	Dynactin subunit 1	Part of the dynactin complex that activates the molecular motor dynein for ultra-processive transport along microtubules.
MED25	Mediator of RNA polymerase II transcription subunit 25	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
RBP7	Retinoid-binding protein 7	Intracellular transport of retinol.
EMD	Emerin	Stabilizes and promotes the formation of a nuclear actin cortical network.
MEX3A	RNA-binding protein MEX3A	RNA binding protein, may be involved in post-transcriptional regulatory mechanisms.
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).
SETX	Helicase senataxin	ATP-dependent 5’->3’ DNA/RNA helicase that preferentially unwinds RNA substrates over DNA, playing a crucial role in resolving R-loops and promoting transcription termination.
DNAJB2	DnaJ homolog subfamily B member 2	Functions as a co-chaperone, regulating the substrate binding and activating the ATPase activity of chaperones of the HSP70/heat shock protein 70 family.
HSPB3	Heat shock protein beta-3	Inhibitor of actin polymerization.
KIF5A	Kinesin heavy chain isoform 5A	Microtubule-dependent motor required for slow axonal transport of neurofilament proteins (NFH, NFM and NFL).
AQP1	Aquaporin-1	Forms a water channel that facilitates the transport of water across cell membranes, playing a crucial role in water homeostasis in various tissues.
LMNA	Prelamin-A/C	Lamins are intermediate filament proteins that assemble into a filamentous meshwork, and which constitute the major components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane.
MME	Neprilysin	Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids.
ATP7A	Copper-transporting ATPase 1	ATP-driven copper (Cu(+)) ion pump that plays an important role in intracellular copper ion homeostasis.
KIF1A	Kinesin-like protein KIF1A	Kinesin motor with a plus-end-directed microtubule motor activity.
PMF1	Polyamine-modulated factor 1	Part of the MIS12 complex which is required for normal chromosome alignment and segregation and kinetochore formation during mitosis.

Protein-family classification

Druggable: 4 · Difficult: 5 · Unknown: 21 · Druggable fraction: 0.13

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	21	1.2×	0.574
Transporter	1	2.6×	0.751
Scaffold/PPI	3	1.7×	0.751
Protease	1	1.2×	0.908
Antibody/Immunoglobulin	1	1.0×	0.908
Transcription factor	2	0.6×	0.927
Enzyme (other)	1	0.4×	0.927

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MYO9B	Other/Unknown	no		IQ_motif_EF-hand-BS, RA_dom, RhoGAP_dom
NEFL	Other/Unknown	no		Intermed_filament_DNA-bd, IF_conserved, IF_rod_dom
RAB7A	Other/Unknown	no		Small_GTPase, Small_GTP-bd, P-loop_NTPase
SH2D2A	Scaffold/PPI	no		SH2, SH2D2A_SH2, SH2_dom_sf
SLC5A7	Transporter	yes		Na/solute_symporter, Na/Glc_symporter_sf, Choline_transporter
BSCL2	Other/Unknown	no		Seipin
KIF1B	Scaffold/PPI	no		FHA_dom, Kinesin_motor_dom, PH_domain
MFN2	Other/Unknown	no		Fzo/mitofusin_HR2, Mitofusin_fam, P-loop_NTPase
AARS1	Other/Unknown	no		Ala-tRNA-lgiase_IIc, DHHA1_dom, Transl_B-barrel_sf
COL12A1	Antibody/Immunoglobulin	yes		VWF_A, FN3_dom, Collagen
MED9	Other/Unknown	no		Med9, Med7/Med21-like, MED9_metazoa
DCTN1	Other/Unknown	no		CAP-Gly_domain, Dynactin, CAP-Gly_dom_sf
KIAA2013	Other/Unknown	no		K2013-like
MED25	Other/Unknown	no		Med25_PTOV, Mediator_Med25_SD1, Mediator_Med25_VWA
RBP7	Other/Unknown	no		Fatty_acid-bd, Lipocln_cytosolic_FA-bd_dom, Calycin
EMD	Other/Unknown	no		LEM_dom, LEM/LEM-like_dom_sf, LEM_emerin
MEX3A	Transcription factor	no		Znf_RING, KH_dom, KH_dom_type_1
GARS1	Enzyme (other)	yes	6.1.1.14	WHEP-TRS_dom, aa-tRNA-synt_IIb, tRNA-synt_gly
SETX	Other/Unknown	no		P-loop_NTPase, DNA2/NAM7_AAA_11, DNA2/NAM7-like_C
HNRNPUL2-BSCL2	Other/Unknown	no
MIR6800	Other/Unknown	no
DNAJB2	Other/Unknown	no		DnaJ_domain, UIM_dom, DnaJ_domain_CS
HSPB3	Other/Unknown	no		Alpha-crystallin/sHSP_animal, A-crystallin/Hsp20_dom, HSP20-like_chaperone
KIF5A	Other/Unknown	no		Kinesin_motor_dom, Kinesin_motor_CS, P-loop_NTPase
AQP1	Other/Unknown	no		MIP, MIP_CS, Aquaporin-like
LMNA	Other/Unknown	no		Lamin_tail_dom, IF_conserved, Lamin_tail_dom_sf
MME	Protease	yes	3.4.24.11	Peptidase_M13, Peptidase_M13_N, Peptidase_M13_C
ATP7A	Transcription factor	no	7.2.2.8	P_typ_ATPase, HMA_dom, HMA_Cu_ion-bd
KIF1A	Scaffold/PPI	no	5.6.1.3	FHA_dom, Kinesin_motor_dom, PH_domain
PMF1	Other/Unknown	no		PMF1/Nnf1

Expression context

Cohort genes with no expression data: 0.

28 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)	30
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	3
right frontal lobe	3
right hemisphere of cerebellum	3
granulocyte	2
left testis	2
lateral nuclear group of thalamus	2
C1 segment of cervical spinal cord	2
stromal cell of endometrium	2
blood	2
male germ line stem cell (sensu Vertebrata) in testis	2
cardiac ventricle	2
heart left ventricle	2
calcaneal tendon	2
cartilage tissue	2
right testis	2
secondary oocyte	2
ventricular zone	2
cerebellar hemisphere	2
sural nerve	1
dorsal root ganglion	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MYO9B	252	ubiquitous	marker	granulocyte, sural nerve, left testis
NEFL	214	broad	marker	dorsal root ganglion, pons, lateral nuclear group of thalamus
RAB7A	297	ubiquitous	marker	stromal cell of endometrium, right lung, C1 segment of cervical spinal cord
SH2D2A	166	broad	marker	granulocyte, male germ line stem cell (sensu Vertebrata) in testis, blood
SLC5A7	101	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, pancreatic ductal cell, primordial germ cell in gonad
BSCL2	149	ubiquitous	marker	superior frontal gyrus, primary visual cortex, pituitary gland
KIF1B	287	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, biceps brachii, medial globus pallidus
MFN2	297	ubiquitous	marker	apex of heart, heart left ventricle, cardiac ventricle
AARS1	301	ubiquitous	marker	endometrium epithelium, type B pancreatic cell, frontal pole
COL12A1	240	ubiquitous	marker	tibia, calcaneal tendon, cartilage tissue
MED9	195	ubiquitous	marker	apex of heart, heart left ventricle, cardiac ventricle
DCTN1	275	ubiquitous	marker	right frontal lobe, prefrontal cortex, right hemisphere of cerebellum
KIAA2013	256	ubiquitous	marker	ileal mucosa, kidney epithelium, oviduct epithelium
MED25	269	ubiquitous	marker	oocyte, secondary oocyte, right testis
RBP7	236	broad	marker	adipose tissue of abdominal region, omental fat pad, peritoneum
EMD	284	ubiquitous	marker	left ovary, left uterine tube, popliteal artery
MEX3A	202	ubiquitous	marker	ganglionic eminence, cortical plate, ventricular zone
GARS1	293	ubiquitous	marker	secondary oocyte, cartilage tissue, lateral nuclear group of thalamus
SETX	281	ubiquitous	marker	right testis, calcaneal tendon, left testis
HNRNPUL2-BSCL2	134		yes	stromal cell of endometrium, ventricular zone, islet of Langerhans
MIR6800	38		yes	gastrocnemius, blood, left adrenal gland cortex
DNAJB2	281	ubiquitous	marker	C1 segment of cervical spinal cord, right hemisphere of cerebellum, cerebellar hemisphere
HSPB3	189	broad	marker	heart right ventricle, left ventricle myocardium, myocardium
KIF5A	198	broad	marker	right frontal lobe, right hemisphere of cerebellum, cerebellar hemisphere
AQP1	283	broad	marker	descending thoracic aorta, ascending aorta, thoracic aorta
LMNA	295	ubiquitous	marker	nipple, mucosa of stomach, skin of abdomen
MME	212	ubiquitous	marker	jejunal mucosa, renal glomerulus, metanephric glomerulus
ATP7A	275	ubiquitous	marker	buccal mucosa cell, trabecular bone tissue, upper leg skin
KIF1A	198	broad	marker	right frontal lobe, postcentral gyrus, parietal lobe
PMF1	278	ubiquitous	marker	hindlimb stylopod muscle, apex of heart, right lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 11.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LMNA	7,173
NEFL	4,644
AQP1	4,259
RAB7A	4,226
ATP7A	3,901
MFN2	3,853
DCTN1	3,654
EMD	3,503
KIF5A	3,241
SETX	3,127

Intra-cohort edges

A	B	Sources
AARS1	GARS1	string_interaction
ATP7A	DNAJB2	biogrid_interaction
BSCL2	GARS1	string_interaction
BSCL2	KIAA2013	biogrid_interaction
BSCL2	LMNA	string_interaction
DCTN1	KIF5A	string_interaction
DCTN1	SETX	string_interaction
EMD	LMNA	intact, string_interaction
HSPB3	NEFL	intact
KIF1A	KIF1B	biogrid_interaction, intact
KIF1B	MFN2	string_interaction

Structural data

PDB: 23 · AlphaFold-only: 5 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LMNA	P02545	28
ATP7A	Q04656	22
KIF1A	Q12756	21
MME	P08473	16
GARS1	P41250	14
DCTN1	Q14203	13
SLC5A7	Q9GZV3	12
MED9	Q9NWA0	11
RAB7A	P51149	10
MED25	Q71SY5	10
AQP1	P29972	10
AARS1	P49588	6
EMD	P50402	6
KIF5A	Q12840	4
PMF1	Q6P1K2	4
MFN2	O95140	3
RBP7	Q96R05	3
MYO9B	Q13459	2
BSCL2	Q96G97	1
KIF1B	O60333	1
COL12A1	Q99715	1
DNAJB2	P25686	1
HSPB3	Q12988	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KIAA2013	Q8IYS2	85.77
NEFL	P07196	73.66
MEX3A	A1L020	65.91
SH2D2A	Q9NP31	61.87
SETX	Q7Z333	52.93

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 152. Enrichment computed across 30 evidence-associated genes (21 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 21 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Depolymerization of the Nuclear Lamina	2	72.5×	0.016	EMD, LMNA
Initiation of Nuclear Envelope (NE) Reformation	2	57.2×	0.016	EMD, LMNA
Kinesins	3	25.5×	0.016	KIF1B, KIF5A, KIF1A
Golgi-to-ER retrograde transport	3	19.0×	0.016	KIF1B, KIF5A, KIF1A
Factors involved in megakaryocyte development and platelet production	4	12.7×	0.016	KIF1B, MFN2, KIF5A, KIF1A
Nuclear Envelope Breakdown	2	43.5×	0.017	EMD, LMNA
Cytosolic tRNA aminoacylation	2	41.8×	0.017	AARS1, GARS1
COPI-dependent Golgi-to-ER retrograde traffic	3	15.8×	0.017	KIF1B, KIF5A, KIF1A
Intra-Golgi and retrograde Golgi-to-ER traffic	3	15.0×	0.017	KIF1B, KIF5A, KIF1A
Defective SLC5A7 in the neurotransmitter release cycle causes distal hereditary motor neuronopathy 7A (HMN7A)	1	543.8×	0.023	SLC5A7
Defective transport by SLC5A7 causes distal hereditary motor neuronopathy 7A (HMN7A)	1	543.8×	0.023	SLC5A7
MHC class II antigen presentation	3	12.8×	0.023	DCTN1, KIF5A, RAB7A
Hemostasis	4	6.9×	0.028	KIF1B, MFN2, KIF5A, KIF1A
Peptide hormone metabolism	2	25.9×	0.029	KIF5A, MME
RHOF GTPase cycle	2	24.7×	0.029	MYO9B, RAB7A
Suppression of autophagy	1	271.9×	0.035	RAB7A
XBP1(S) activates chaperone genes	2	20.5×	0.037	DCTN1, LMNA
RHOD GTPase cycle	2	19.4×	0.037	EMD, RAB7A
RAC1 GTPase cycle	3	8.7×	0.037	EMD, MYO9B, RAB7A
Respiratory Syncytial Virus Infection Pathway	2	18.8×	0.038	MED9, MED25
Breakdown of the nuclear lamina	1	181.3×	0.040	LMNA
Ion influx/efflux at host-pathogen interface	1	135.9×	0.048	ATP7A
SLIT2:ROBO1 increases RHOA activity	1	135.9×	0.048	MYO9B
RSV-host interactions	2	14.9×	0.048	MED9, MED25
Adipogenesis	2	14.9×	0.048	MED9, MED25
RHOG GTPase cycle	2	14.1×	0.051	EMD, RAB7A
Miro GTPase Cycle	1	108.8×	0.052	MFN2
Regulation of lipid metabolism by PPARalpha	2	13.4×	0.052	MED9, MED25
Transcriptional regulation of white adipocyte differentiation	2	12.4×	0.059	MED9, MED25
RAC2 GTPase cycle	2	12.1×	0.059	EMD, RAB7A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 26 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
retrograde neuronal dense core vesicle transport	3	388.9×	1e-05	KIF1B, KIF5A, KIF1A
neuron cellular homeostasis	3	52.5×	0.004	DCTN1, DNAJB2, ATP7A
response to unfolded protein	3	34.7×	0.009	MFN2, DNAJB2, HSPB3
synaptic vesicle recycling via endosome	1	648.1×	0.027	RAB7A
intermediate filament polymerization or depolymerization	1	648.1×	0.027	NEFL
positive regulation of termination of DNA-templated transcription	1	648.1×	0.027	SETX
neuropeptide processing	1	648.1×	0.027	MME
metanephric descending thin limb development	1	648.1×	0.027	AQP1
metanephric proximal straight tubule development	1	648.1×	0.027	AQP1
metanephric proximal convoluted tubule segment 2 development	1	648.1×	0.027	AQP1
regulation of cytoplasmic translational fidelity	1	648.1×	0.027	AARS1
regulation of protein folding	1	648.1×	0.027	DNAJB2
positive regulation of mediator complex assembly	1	648.1×	0.027	MED25
tRNA aminoacylation for protein translation	2	64.8×	0.027	AARS1, GARS1
camera-type eye morphogenesis	2	58.9×	0.027	MFN2, AQP1
nuclear migration	2	56.4×	0.027	DCTN1, LMNA
neuromuscular synaptic transmission	2	46.3×	0.027	SLC5A7, KIF1B
anterograde axonal transport	2	44.7×	0.027	NEFL, KIF1A
negative regulation of fibroblast proliferation	2	38.1×	0.027	MED25, EMD
alanyl-tRNA aminoacylation	1	324.1×	0.028	AARS1
epidermal growth factor catabolic process	1	324.1×	0.028	RAB7A
carbon dioxide transmembrane transport	1	324.1×	0.028	AQP1
obsolete negative regulation of catecholamine metabolic process	1	324.1×	0.028	ATP7A
creatinine metabolic process	1	324.1×	0.028	MME
corticotropin secretion	1	324.1×	0.028	AQP1
mitochondrial glycyl-tRNA aminoacylation	1	324.1×	0.028	GARS1
metanephric glomerulus vasculature development	1	324.1×	0.028	AQP1
negative regulation of protein deubiquitination	1	324.1×	0.028	DNAJB2
neurotransmitter receptor transport, postsynaptic endosome to lysosome	1	324.1×	0.028	RAB7A
response to sodium arsenite	1	324.1×	0.028	NEFL

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 3 · Phased (≥1): 4 · Undrugged: 26

Druggability breadth: 16 of 30 evidence-associated genes (53%) 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
LMNA	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LMNA	823	4
MME	4	2
SLC5A7	1	3
GARS1	1	3
MYO9B	0	0
NEFL	0	0
RAB7A	0	0
SH2D2A	0	0
BSCL2	0	0
KIF1B	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	LMNA
PHENYLBUTAZONE	4	LMNA
CEFOTAXIME SODIUM	4	LMNA
DIENESTROL	4	LMNA
IFOSFAMIDE	4	LMNA
PROGESTERONE	4	LMNA
CLOTRIMAZOLE	4	LMNA
DAPSONE	4	LMNA
AMINOCAPROIC ACID	4	LMNA
FLUCONAZOLE	4	LMNA
COLCHICINE	4	LMNA
NABUMETONE	4	LMNA
OXAPROZIN	4	LMNA
BUMETANIDE	4	LMNA
GLIPIZIDE	4	LMNA
BROMFENAC	4	LMNA
ROPIVACAINE	4	LMNA
TIZANIDINE	4	LMNA
METAXALONE	4	LMNA
CARBAMAZEPINE	4	LMNA
SALMETEROL XINAFOATE	4	LMNA
AMIODARONE HYDROCHLORIDE	4	LMNA
METHYL SALICYLATE	4	LMNA
DIBUCAINE	4	LMNA
PHENELZINE	4	LMNA
HYDROCORTISONE ACETATE	4	LMNA
BRETYLIUM TOSYLATE	4	LMNA
IMIPRAMINE	4	LMNA
FURAZOLIDONE	4	LMNA
DROPERIDOL	4	LMNA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
MME	125	Binding:110, ADMET:15
SLC5A7	34	Binding:24, Functional:10
RAB7A	33	Binding:33
LMNA	12	Binding:9, Functional:3
ATP7A	11	Binding:11
GARS1	8	Binding:8
KIF5A	8	Binding:8
AQP1	8	Binding:8
MFN2	3	Binding:3
MED25	3	Binding:3
AARS1	2	Binding:2
KIF1A	2	Binding:2
SH2D2A	1	Binding:1
KIF1B	1	Binding:1
DCTN1	1	Binding:1
EMD	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GARS1	6.1.1.14	glycine-tRNA ligase
MME	3.4.24.11	neprilysin
ATP7A	7.2.2.8, 7.2.2.9	P-type Cu+ transporter, P-type Cu2+ transporter
KIF1A	5.6.1.3	plus-end-directed kinesin ATPase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
MME	125

Pharmacogenomics

Cohort genes with a PharmGKB record: 28; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
BEPRIDIL	4	LMNA
PHENYLBUTAZONE	4	LMNA
CEFOTAXIME SODIUM	4	LMNA
DIENESTROL	4	LMNA
IFOSFAMIDE	4	LMNA
PROGESTERONE	4	LMNA
CLOTRIMAZOLE	4	LMNA
DAPSONE	4	LMNA
AMINOCAPROIC ACID	4	LMNA
FLUCONAZOLE	4	LMNA
COLCHICINE	4	LMNA
NABUMETONE	4	LMNA
OXAPROZIN	4	LMNA
BUMETANIDE	4	LMNA
GLIPIZIDE	4	LMNA
BROMFENAC	4	LMNA
ROPIVACAINE	4	LMNA
TIZANIDINE	4	LMNA
METAXALONE	4	LMNA
CARBAMAZEPINE	4	LMNA
SALMETEROL XINAFOATE	4	LMNA
AMIODARONE HYDROCHLORIDE	4	LMNA
METHYL SALICYLATE	4	LMNA
DIBUCAINE	4	LMNA
PHENELZINE	4	LMNA
HYDROCORTISONE ACETATE	4	LMNA
BRETYLIUM TOSYLATE	4	LMNA
IMIPRAMINE	4	LMNA
FURAZOLIDONE	4	LMNA
DROPERIDOL	4	LMNA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	LMNA
B	Phased (≥1) drug, not yet approved	3	SLC5A7, GARS1, MME
C	Druggable family + PDB, no drug	1	COL12A1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	25	MYO9B, NEFL, RAB7A, SH2D2A, BSCL2, KIF1B, MFN2, AARS1, MED9, DCTN1 (+15 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BSCL2	0	LMNA
EMD	1	LMNA
MYO9B	0	—
NEFL	0	—
RAB7A	33	—
SH2D2A	1	—
KIF1B	1	—
MFN2	3	—
AARS1	2	—
COL12A1	0	—
MED9	0	—
DCTN1	1	—
KIAA2013	0	—
MED25	3	—
RBP7	0	—
MEX3A	0	—
SETX	0	—
HNRNPUL2-BSCL2	0	—
MIR6800	0	—
DNAJB2	0	—
HSPB3	0	—
KIF5A	8	—
AQP1	8	—
ATP7A	11	—
KIF1A	2	—
PMF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

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