Charcot-Marie-Tooth disease type 4

disease

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Also known as AR-CMT1autosomal recessive demyelinating Charcot-Marie-ToothCMT4

Summary

Charcot-Marie-Tooth disease type 4 (MONDO:0018995) is a disease (an umbrella term covering 12 Mondo subtypes) caused by PRX (GenCC Definitive), with 26 cohort genes.

At a glance

Prevalence: 1-5 / 10 000 (Europe) [Orphanet-validated]
Causal gene: PRX (GenCC Definitive)
Umbrella term: 12 Mondo subtypes
Cohort genes: 26
ClinVar variants: 6,088

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000		Europe	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease type 4
Mondo ID	MONDO:0018995
Orphanet	64749
DOID	DOID:0050541
SNOMED CT	715795005
UMLS	C4082197
MedGen	905419
GARD	0012440
Is cancer (heuristic)	no

Also known as: AR-CMT1 · autosomal recessive demyelinating Charcot-Marie-Tooth · CMT4

Data availability: 6,088 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 12 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 4

Subtypes (12): Charcot-Marie-Tooth disease type 4A, Charcot-Marie-Tooth disease type 4B1, Charcot-Marie-Tooth disease type 4D, Charcot-Marie-Tooth disease type 4C, Charcot-Marie-Tooth disease type 4B2, Charcot-Marie-Tooth disease type 4E, Charcot-Marie-Tooth disease type 4G, Charcot-Marie-Tooth disease type 4H, Charcot-Marie-Tooth disease type 4J, Charcot-Marie-Tooth disease type 4F, Charcot-Marie-Tooth disease type 4B3, Charcot-Marie-Tooth disease type 4K

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:

280 likely benign, 267 uncertain significance, 27 pathogenic, 17 conflicting classifications of pathogenicity, 8 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1011	NM_001370298.3(FGD4):c.1081C>T (p.Arg361Ter)	FGD4	Pathogenic	criteria provided, multiple submitters, no conflicts
1016	NM_001370298.3(FGD4):c.1234C>T (p.Arg412Ter)	FGD4	Pathogenic	criteria provided, single submitter
1072959	NM_001370298.3(FGD4):c.2079G>A (p.Trp693Ter)	FGD4	Pathogenic	criteria provided, single submitter
1075631	NM_001370298.3(FGD4):c.616del (p.Gln206fs)	FGD4	Pathogenic	criteria provided, single submitter
1075824	NM_001370298.3(FGD4):c.2252_2253del (p.Cys751fs)	FGD4	Pathogenic	criteria provided, single submitter
1070629	NM_014845.6(FIG4):c.531T>G (p.Tyr177Ter)	FIG4	Pathogenic	criteria provided, multiple submitters, no conflicts
1073202	NM_014845.6(FIG4):c.2161del (p.Thr721fs)	FIG4	Pathogenic	criteria provided, single submitter
1073230	NM_014845.6(FIG4):c.1445_1452del (p.Leu482fs)	FIG4	Pathogenic	criteria provided, single submitter
1075927	NM_014845.6(FIG4):c.783del (p.Ile262fs)	FIG4	Pathogenic	criteria provided, single submitter
1076817	NM_030962.4(SBF2):c.1879G>T (p.Glu627Ter)	LOC101928008	Pathogenic	criteria provided, single submitter
1069360	NM_016156.6(MTMR2):c.1318C>T (p.Arg440Ter)	MTMR2	Pathogenic	criteria provided, single submitter
1070808	NM_016156.6(MTMR2):c.1459_1460del (p.Val487fs)	MTMR2	Pathogenic	criteria provided, single submitter
1073568	NM_006096.4(NDRG1):c.205+2T>A	NDRG1	Pathogenic	criteria provided, single submitter
1075484	NM_181882.3(PRX):c.1171del (p.Leu391fs)	PRX	Pathogenic	criteria provided, single submitter
1075829	NM_181882.3(PRX):c.205C>T (p.Arg69Ter)	PRX	Pathogenic	criteria provided, single submitter
1072400	NC_000011.9:g.(?9989878)(9990102_?)del	SBF2	Pathogenic	criteria provided, single submitter
1072401	NC_000011.9:g.(?10215443)(10215540_?)del	SBF2	Pathogenic	criteria provided, single submitter
1076239	NC_000011.9:g.(?9809171)(9812240_?)del	SBF2	Pathogenic	criteria provided, single submitter
1011026	NM_024577.4(SH3TC2):c.3508_3516del (p.His1170_Leu1172del)	SH3TC2	Pathogenic	criteria provided, single submitter
1012529	NM_024577.4(SH3TC2):c.819dup (p.Lys274Ter)	SH3TC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066688	NM_024577.4(SH3TC2):c.3327+1G>A	SH3TC2	Pathogenic	criteria provided, single submitter
1068543	NM_024577.4(SH3TC2):c.676C>T (p.Gln226Ter)	SH3TC2	Pathogenic	criteria provided, single submitter
1070097	NM_024577.4(SH3TC2):c.3078C>A (p.Cys1026Ter)	SH3TC2	Pathogenic	criteria provided, single submitter
1073106	NM_024577.4(SH3TC2):c.1556_1557insCGGGTGGATCATGAGGTCAGGAGATCGAGACCATCCTGGCTAANNNNNNNNNNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAAAAAAGAAAGTGGGCCAAG (p.Lys519delinsAsnGlyTrpIleMetArgSerGlyAspArgAspHisProGlyTer)	SH3TC2	Pathogenic	criteria provided, single submitter
1075273	NM_024577.4(SH3TC2):c.1557_1558insGCCGGGCGCGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGGCCGAAGCGGGTGGATCATGAGGTCAGGAGATCGAGACCATCCTGGCTAACAAGGTGAAACCCCGTCTCTACTAANNNNNNNNNNAAAAAAAAAAAAAAAAAAAAGAAAGTGGGCCAAG (p.Lys520delinsAlaGlyArgGlyGlySerCysLeuTer)	SH3TC2	Pathogenic	criteria provided, single submitter
1075741	NC_000005.9:g.(?148360713)(148443737_?)del	SH3TC2	Pathogenic	criteria provided, single submitter
1076119	NM_024577.4(SH3TC2):c.1546A>T (p.Lys516Ter)	SH3TC2	Pathogenic	criteria provided, single submitter
1076648	NM_024577.4(SH3TC2):c.2775G>A (p.Trp925Ter)	SH3TC2	Pathogenic	criteria provided, single submitter
1068289	NM_014845.6(FIG4):c.876+2T>G	FIG4	Likely pathogenic	criteria provided, single submitter
1066335	NM_030962.4(SBF2):c.5038-2A>G	LOC105369149	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 47 · 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
PRDX6	Definitive	Autosomal recessive	Charcot-Marie-Tooth disease type 4	7
PRX	Definitive	Autosomal recessive	Charcot-Marie-Tooth disease type 4	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRX	Orphanet:64748	Dejerine-Sottas syndrome
PRX	Orphanet:99952	Charcot-Marie-Tooth disease type 4F
SBF1	Orphanet:363981	Charcot-Marie-Tooth disease type 4B3
GDAP1	Orphanet:101097	Autosomal recessive Charcot-Marie-Tooth disease with hoarseness
GDAP1	Orphanet:101102	Charcot-Marie-Tooth disease type 2H
GDAP1	Orphanet:217055	Autosomal recessive intermediate Charcot-Marie-Tooth disease type A
GDAP1	Orphanet:99944	Autosomal dominant Charcot-Marie-Tooth disease type 2K
GDAP1	Orphanet:99948	Charcot-Marie-Tooth disease type 4A
KIF1B	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
KIF1B	Orphanet:99946	Autosomal dominant Charcot-Marie-Tooth disease type 2A1
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
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
PLD3	Orphanet:589522	Spinocerebellar ataxia type 46
TRPV4	Orphanet:1216	Autosomal dominant congenital benign spinal muscular atrophy
TRPV4	Orphanet:263482	Spondyloepimetaphyseal dysplasia, Maroteaux type
TRPV4	Orphanet:2635	Metatropic dysplasia
TRPV4	Orphanet:431255	Scapuloperoneal spinal muscular atrophy
TRPV4	Orphanet:85169	Familial digital arthropathy-brachydactyly
TRPV4	Orphanet:86820	Familial avascular necrosis of femoral head
TRPV4	Orphanet:93304	Autosomal dominant brachyolmia
TRPV4	Orphanet:93314	Spondylometaphyseal dysplasia, Kozlowski type
TRPV4	Orphanet:99937	Autosomal dominant Charcot-Marie-Tooth disease type 2C
FGD4	Orphanet:99954	Charcot-Marie-Tooth disease type 4H
SBF2	Orphanet:99956	Charcot-Marie-Tooth disease type 4B2
MORC2	Orphanet:466768	Autosomal dominant Charcot-Marie-Tooth disease type 2Z
LRSAM1	Orphanet:300319	Charcot-Marie-Tooth disease type 2P
SH3TC2	Orphanet:99949	Charcot-Marie-Tooth disease type 4C
DYNC1H1	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
DYNC1H1	Orphanet:209341	DYNC1H1-related autosomal dominant childhood-onset proximal spinal muscular atrophy
DYNC1H1	Orphanet:284232	Autosomal dominant Charcot-Marie-Tooth disease type 2O
DNM1L	Orphanet:330050	DNM1L-related encephalopathy due to mitochondrial and peroxisomal fission defect
DNM1L	Orphanet:98673	Autosomal dominant optic atrophy, classic form
AK9	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
HSPB1	Orphanet:139525	Distal hereditary motor neuropathy type 2
HSPB1	Orphanet:99940	Autosomal dominant Charcot-Marie-Tooth disease type 2F
IGHMBP2	Orphanet:443073	Charcot-Marie-Tooth disease type 2S
IGHMBP2	Orphanet:98920	Spinal muscular atrophy with respiratory distress type 1
SEPTIN9	Orphanet:2901	Neuralgic amyotrophy
MTMR2	Orphanet:99955	Charcot-Marie-Tooth disease type 4B1
NDRG1	Orphanet:99950	Charcot-Marie-Tooth disease type 4D

Cohort genes → proteins

26 cohort genes, 25 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	26

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PRX	HGNC:13797	ENSG00000105227	Q9BXM0	Periaxin	gencc,clinvar
PRDX6	HGNC:16753	ENSG00000117592	P30041	Peroxiredoxin-6	gencc,clinvar
SBF1	HGNC:10542	ENSG00000100241	O95248	Myotubularin-related protein 5	clinvar
CCN4	HGNC:12769	ENSG00000104415	O95388	CCN family member 4	clinvar
GDAP1	HGNC:15968	ENSG00000104381	Q8TB36	Ganglioside-induced differentiation-associated protein 1	clinvar
AFG1L	HGNC:16411	ENSG00000135537	Q8WV93	AFG1-like ATPase	clinvar
KIF1B	HGNC:16636	ENSG00000054523	O60333	Kinesin-like protein KIF1B	clinvar
FIG4	HGNC:16873	ENSG00000112367	Q92562	Polyphosphoinositide phosphatase	clinvar
MFN2	HGNC:16877	ENSG00000116688	O95140	Mitofusin-2	clinvar
PLD3	HGNC:17158	ENSG00000105223	Q8IV08	5’-3’ exonuclease PLD3	clinvar
TRPV4	HGNC:18083	ENSG00000111199	Q9HBA0	Transient receptor potential cation channel subfamily V member 4	clinvar
FGD4	HGNC:19125	ENSG00000139132	Q96M96	FYVE, RhoGEF and PH domain-containing protein 4	clinvar
SBF2	HGNC:2135	ENSG00000133812	Q86WG5	Myotubularin-related protein 13	clinvar
MORC2	HGNC:23573	ENSG00000133422	Q9Y6X9	ATPase MORC2	clinvar
PHF20L1	HGNC:24280	ENSG00000129292	A8MW92	PHD finger protein 20-like protein 1	clinvar
LRSAM1	HGNC:25135	ENSG00000148356	Q6UWE0	E3 ubiquitin-protein ligase LRSAM1	clinvar
SBF2-AS1	HGNC:27438	ENSG00000246273		SBF2 antisense RNA 1	clinvar
SH3TC2	HGNC:29427	ENSG00000169247	Q8TF17	SH3 domain and tetratricopeptide repeat-containing protein 2	clinvar
DYNC1H1	HGNC:2961	ENSG00000197102	Q14204	Cytoplasmic dynein 1 heavy chain 1	clinvar
DNM1L	HGNC:2973	ENSG00000087470	O00429	Dynamin-1-like protein	clinvar
AK9	HGNC:33814	ENSG00000155085	Q5TCS8	Adenylate kinase 9	clinvar
HSPB1	HGNC:5246	ENSG00000106211	P04792	Heat shock protein beta-1	clinvar
IGHMBP2	HGNC:5542	ENSG00000132740	P38935	DNA-binding protein SMUBP-2	clinvar
SEPTIN9	HGNC:7323	ENSG00000184640	Q9UHD8	Septin-9	clinvar
MTMR2	HGNC:7450	ENSG00000087053	Q13614	Phosphatidylinositol-3,5-bisphosphate 3-phosphatase MTMR2	clinvar
NDRG1	HGNC:7679	ENSG00000104419	Q92597	Protein NDRG1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
PRDX6	Peroxiredoxin-6	Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively.
SBF1	Myotubularin-related protein 5	Acts as an adapter for the phosphatase MTMR2 to regulate MTMR2 catalytic activity and subcellular location.
CCN4	CCN family member 4	Downstream regulator in the Wnt/Frizzled-signaling pathway.
GDAP1	Ganglioside-induced differentiation-associated protein 1	Regulates the mitochondrial network by promoting mitochondrial fission.
AFG1L	AFG1-like ATPase	Putative mitochondrial ATPase.
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.
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).
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.
TRPV4	Transient receptor potential cation channel subfamily V member 4	Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity.
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.
SBF2	Myotubularin-related protein 13	Guanine nucleotide exchange factor (GEF) which activates RAB21 and possibly RAB28.
MORC2	ATPase MORC2	ATP-dependent chromatin remodeler essential for epigenetic silencing by the HUSH (human silencing hub) complex.
PHF20L1	PHD finger protein 20-like protein 1	Is a negative regulator of proteasomal degradation of a set of methylated proteins, including DNMT1 and SOX2.
LRSAM1	E3 ubiquitin-protein ligase LRSAM1	E3 ubiquitin-protein ligase that mediates monoubiquitination of TSG101 at multiple sites, leading to inactivate the ability of TSG101 to sort endocytic (EGF receptors) and exocytic (HIV-1 viral proteins) cargos.
SH3TC2	SH3 domain and tetratricopeptide repeat-containing protein 2	Is involved in nerve myelination and is required for the integrity of nodes of Ranvier.
DYNC1H1	Cytoplasmic dynein 1 heavy chain 1	Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules.
DNM1L	Dynamin-1-like protein	Functions in mitochondrial and peroxisomal division.
AK9	Adenylate kinase 9	Broad-specificity nucleoside phosphate kinase involved in cellular nucleotide homeostasis by catalyzing nucleoside-phosphate interconversions.
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.
IGHMBP2	DNA-binding protein SMUBP-2	5’ to 3’ helicase that unwinds RNA and DNA duplexes in an ATP-dependent reaction.
SEPTIN9	Septin-9	Filament-forming cytoskeletal GTPase.
MTMR2	Phosphatidylinositol-3,5-bisphosphate 3-phosphatase MTMR2	Lipid phosphatase that specifically dephosphorylates the D-3 position of phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate, generating phosphatidylinositol and phosphatidylinositol 5-phosphate.
NDRG1	Protein NDRG1	Stress-responsive protein involved in hormone responses, cell growth, and differentiation.

Protein-family classification

Druggable: 6 · Difficult: 8 · Unknown: 12 · Druggable fraction: 0.23

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
Phosphatase	3	9.7×	0.021
Ion channel	1	4.3×	0.313
Scaffold/PPI	3	2.0×	0.313
Transcription factor	5	1.6×	0.313
Enzyme (other)	2	0.9×	0.780
Other/Unknown	12	0.8×	0.883

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRX	Scaffold/PPI	no		PDZ, PDZ_sf, Myelin_sheath_structural
PRDX6	Enzyme (other)	yes	1.11.1.27	AhpC/TSA, Thioredoxin_domain, Peroxiredoxin_C
SBF1	Phosphatase	yes	3.1.3.16	cDENN_dom, PH_domain, GRAM
CCN4	Other/Unknown	no		IGFBP-like, TSP1_rpt, VWF_dom
GDAP1	Other/Unknown	no		Glutathione_S-Trfase_N, Glutathione-S-Trfase_C-like, GST_C_GDAP1
AFG1L	Other/Unknown	no		ATPase_AFG1-like, P-loop_NTPase
KIF1B	Scaffold/PPI	no		FHA_dom, Kinesin_motor_dom, PH_domain
FIG4	Other/Unknown	no		SAC_dom, Fig4-like
MFN2	Other/Unknown	no		Fzo/mitofusin_HR2, Mitofusin_fam, P-loop_NTPase
PLD3	Other/Unknown	no		PLipase_D/transphosphatidylase, PLDc_3, Diverse_PLD-related
TRPV4	Ion channel	yes		Ankyrin_rpt, Ion_trans_dom, TrpV1-4
FGD4	Transcription factor	no		DH_dom, Znf_FYVE, PH_domain
SBF2	Phosphatase	yes		cDENN_dom, PH_domain, GRAM
MORC2	Transcription factor	no		Znf_CW, HATPase_C_sf, Morc_S5
PHF20L1	Transcription factor	no		Tudor, Znf_FYVE_PHD, Znf_RING/FYVE/PHD
LRSAM1	Transcription factor	no		Leu-rich_rpt, SAM, Znf_RING
SBF2-AS1	Other/Unknown	no
SH3TC2	Scaffold/PPI	no		SH3_domain, TPR-like_helical_dom_sf, TPR_rpt
DYNC1H1	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
DNM1L	Enzyme (other)	yes	3.6.5.5	Dynamin_stalk, Dynamin_GTPase, GED
AK9	Other/Unknown	no		Adenylat/UMP-CMP_kin, AAA+_ATPase, P-loop_NTPase
HSPB1	Other/Unknown	no		Alpha-crystallin/sHSP_animal, A-crystallin/Hsp20_dom, HSP20-like_chaperone
IGHMBP2	Transcription factor	no	3.6.4.12	Znf_AN1, R3H_dom, AAA+_ATPase
SEPTIN9	Other/Unknown	no		Septin, P-loop_NTPase, G_SEPTIN_dom
MTMR2	Phosphatase	yes	3.1.3.64	Tyr_Pase_dom, Tyr_Pase_cat, GRAM
NDRG1	Other/Unknown	no		NDRG, AB_hydrolase_fold

Expression context

Cohort genes with no expression data: 0.

18 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)	26
unknown	0

Top tissues across cohort

Tissue	Cohort genes
sural nerve	4
male germ line stem cell (sensu Vertebrata) in testis	3
calcaneal tendon	3
sperm	3
olfactory bulb	2
mucosa of stomach	2
left testis	2
right testis	2
cartilage tissue	2
endothelial cell	2
medial globus pallidus	2
lateral nuclear group of thalamus	2
apex of heart	2
lower esophagus mucosa	2
ileal mucosa	2
male germ cell	2
cortical plate	2
trigeminal ganglion	1
corpus epididymis	1
gastrocnemius	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRX	258	ubiquitous	marker	olfactory bulb, trigeminal ganglion, sural nerve
PRDX6	295	ubiquitous	marker	corpus epididymis, gastrocnemius, mucosa of stomach
SBF1	278	ubiquitous	yes	left testis, right testis, right lobe of thyroid gland
CCN4	177	broad	yes	cartilage tissue, tibia, mucosa of paranasal sinus
GDAP1	244	ubiquitous	yes	endothelial cell, secondary oocyte, oocyte
AFG1L	164	ubiquitous	yes	left testis, right testis, male germ line stem cell (sensu Vertebrata) in testis
KIF1B	287	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, biceps brachii, medial globus pallidus
FIG4	295	ubiquitous	marker	middle temporal gyrus, endothelial cell, lateral nuclear group of thalamus
MFN2	297	ubiquitous	marker	apex of heart, heart left ventricle, cardiac ventricle
PLD3	282	ubiquitous	marker	adenohypophysis, pituitary gland, right frontal lobe
TRPV4	171	ubiquitous	marker	cartilage tissue, lower esophagus mucosa, olfactory segment of nasal mucosa
FGD4	252	ubiquitous	marker	jejunal mucosa, calcaneal tendon, ileal mucosa
SBF2	257	ubiquitous	marker	epithelial cell of pancreas, colonic epithelium, calcaneal tendon
MORC2	292	ubiquitous	yes	cervix squamous epithelium, sperm, male germ cell
PHF20L1	278	ubiquitous	marker	adrenal tissue, calcaneal tendon, cortical plate
LRSAM1	192	ubiquitous	yes	apex of heart, sural nerve, skin of leg
SBF2-AS1	165	ubiquitous	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, stromal cell of endometrium
SH3TC2	168	broad	marker	corpus callosum, sural nerve, C1 segment of cervical spinal cord
DYNC1H1	290	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone
DNM1L	295	ubiquitous	marker	lateral nuclear group of thalamus, substantia nigra pars compacta, sperm
AK9	221	ubiquitous	marker	sural nerve, male germ line stem cell (sensu Vertebrata) in testis, right uterine tube
HSPB1	299	ubiquitous	marker	lower esophagus mucosa, ascending aorta, thoracic aorta
IGHMBP2	189	ubiquitous	yes	mucosa of stomach, esophagogastric junction muscularis propria, lower esophagus muscularis layer
SEPTIN9	293	ubiquitous	marker	ileal mucosa, granulocyte, thymus
MTMR2	288	ubiquitous	marker	sperm, parotid gland, male germ cell
NDRG1	294	ubiquitous	marker	olfactory bulb, medial globus pallidus, tibial nerve

Protein interactions among cohort

Intra-cohort edges: 44.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HSPB1	5,491
DNM1L	4,801
DYNC1H1	4,215
PRDX6	4,106
MFN2	3,853
AK9	2,977
NDRG1	2,778
KIF1B	2,257
SEPTIN9	2,119
LRSAM1	2,095

Intra-cohort edges

A	B	Sources
CCN4	NDRG1	string_interaction
DNM1L	MFN2	string_interaction
DNM1L	PRDX6	intact
DYNC1H1	IGHMBP2	string_interaction
FGD4	FIG4	string_interaction
FGD4	GDAP1	string_interaction
FGD4	LRSAM1	string_interaction
FGD4	MORC2	string_interaction
FGD4	MTMR2	string_interaction
FGD4	NDRG1	string_interaction
FGD4	SBF1	string_interaction
FGD4	SBF2	string_interaction
FGD4	SH3TC2	string_interaction
FIG4	MTMR2	string_interaction
FIG4	SBF1	string_interaction
FIG4	SBF2	string_interaction
FIG4	SH3TC2	string_interaction
GDAP1	IGHMBP2	string_interaction
GDAP1	LRSAM1	string_interaction
GDAP1	MFN2	string_interaction
GDAP1	MORC2	string_interaction
GDAP1	MTMR2	string_interaction
GDAP1	NDRG1	string_interaction
GDAP1	SBF1	string_interaction
GDAP1	SBF2	string_interaction
GDAP1	SH3TC2	string_interaction
IGHMBP2	LRSAM1	string_interaction
IGHMBP2	MORC2	string_interaction
IGHMBP2	SH3TC2	string_interaction
KIF1B	MFN2	string_interaction
LRSAM1	MTMR2	string_interaction
LRSAM1	SBF2	string_interaction
LRSAM1	SH3TC2	string_interaction
MORC2	SH3TC2	string_interaction
MTMR2	NDRG1	string_interaction
MTMR2	PRX	string_interaction
MTMR2	SBF1	biogrid_interaction, intact, string_interaction
MTMR2	SBF2	biogrid_interaction, intact, string_interaction
MTMR2	SH3TC2	string_interaction
NDRG1	SBF2	string_interaction
NDRG1	SH3TC2	string_interaction
SBF1	SBF2	biogrid_interaction, intact
SBF1	SH3TC2	string_interaction
SBF2	SH3TC2	string_interaction

Structural data

PDB: 17 · AlphaFold-only: 8 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DYNC1H1	Q14204	97
TRPV4	Q9HBA0	19
DNM1L	O00429	11
MORC2	Q9Y6X9	9
PHF20L1	A8MW92	9
GDAP1	Q8TB36	8
PLD3	Q8IV08	7
HSPB1	P04792	6
MTMR2	Q13614	5
IGHMBP2	P38935	4
PRDX6	P30041	3
MFN2	O95140	3
SEPTIN9	Q9UHD8	3
PRX	Q9BXM0	1
KIF1B	O60333	1
FIG4	Q92562	1
NDRG1	Q92597	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AFG1L	Q8WV93	78.92
SH3TC2	Q8TF17	78.63
LRSAM1	Q6UWE0	78.47
CCN4	O95388	77.16
SBF1	O95248	74.72
SBF2	Q86WG5	73.74
AK9	Q5TCS8	73.70
FGD4	Q96M96	70.85

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 85. Enrichment computed across 26 evidence-associated genes (20 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 20 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Synthesis of PIPs at the ER membrane	2	228.4×	0.001	SBF1, MTMR2
PI Metabolism	3	53.5×	0.001	SBF1, SBF2, MTMR2
Phospholipid metabolism	3	30.1×	0.004	SBF1, SBF2, MTMR2
Synthesis of PIPs at the late endosome membrane	2	95.2×	0.004	FIG4, MTMR2
Synthesis of PIPs at the early endosome membrane	2	71.4×	0.006	FIG4, MTMR2
Rab regulation of trafficking	2	36.8×	0.019	SBF1, SBF2
Metabolism of lipids	4	6.3×	0.039	SBF1, SBF2, MORC2, MTMR2
Synthesis of PIPs at the plasma membrane	2	21.1×	0.042	SBF2, MTMR2
Miro GTPase Cycle	1	114.2×	0.082	MFN2
RHOT2 GTPase cycle	1	81.6×	0.094	MFN2
RAB GEFs exchange GTP for GDP on RABs	2	12.4×	0.094	SBF1, SBF2
Synthesis of PG	1	63.4×	0.103	PLD3
Membrane Trafficking	3	5.6×	0.103	SBF1, KIF1B, SBF2
Mitophagy	1	51.9×	0.108	MFN2
Vesicle-mediated transport	3	5.2×	0.108	SBF1, KIF1B, SBF2
Metabolism	5	2.9×	0.129	SBF1, SBF2, MORC2, AK9, MTMR2
TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain	1	38.1×	0.130	NDRG1
Synthesis of PIPs at the Golgi membrane	1	31.7×	0.147	FIG4
TP53 Regulates Transcription of Cell Death Genes	1	27.2×	0.150	NDRG1
Class I peroxisomal membrane protein import	1	25.9×	0.150	GDAP1
Apoptotic execution phase	1	23.8×	0.150	DNM1L
Role of phospholipids in phagocytosis	1	22.8×	0.150	PLD3
Fatty acyl-CoA biosynthesis	1	22.0×	0.150	MORC2
TRP channels	1	20.4×	0.150	TRPV4
Attenuation phase	1	20.4×	0.150	HSPB1
HSF1 activation	1	19.0×	0.150	HSPB1
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	18.4×	0.150	PRX
Regulation of endogenous retroelements	1	18.4×	0.150	MORC2
Interconversion of nucleotide di- and triphosphates	1	17.8×	0.150	AK9
PINK1-PRKN Mediated Mitophagy	1	17.8×	0.150	MFN2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 24 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
peripheral nervous system myelin maintenance	3	191.5×	9e-05	PRX, SH3TC2, NDRG1
negative regulation of myelination	2	156.0×	0.004	FIG4, MTMR2
myelin assembly	2	156.0×	0.004	FIG4, MTMR2
phosphatidylinositol biosynthetic process	3	45.8×	0.004	SBF1, FIG4, MTMR2
mitochondrial fission	2	87.8×	0.010	GDAP1, DNM1L
negative regulation of endocytosis	2	78.0×	0.010	LRSAM1, MTMR2
mitochondrial fusion	2	70.2×	0.011	GDAP1, MFN2
phosphatidylinositol dephosphorylation	2	54.0×	0.016	FIG4, MTMR2
obsolete protein targeting to mitochondrion	2	48.4×	0.018	GDAP1, MFN2
hyperosmotic salinity response	1	702.2×	0.021	TRPV4
negative regulation of protein kinase C signaling	1	702.2×	0.021	HSPB1
blood vessel endothelial cell delamination	1	702.2×	0.021	TRPV4
regulation of ERBB signaling pathway	1	702.2×	0.021	SH3TC2
negative regulation of receptor catabolic process	1	702.2×	0.021	MTMR2
vasopressin secretion	1	351.1×	0.027	TRPV4
positive regulation of striated muscle contraction	1	351.1×	0.027	TRPV4
CDP biosynthetic process	1	351.1×	0.027	AK9
regulation of response to osmotic stress	1	351.1×	0.027	TRPV4
mitochondrial membrane fission	1	351.1×	0.027	DNM1L
calcium ion import into cytosol	1	351.1×	0.027	TRPV4
regulation of ATP metabolic process	1	351.1×	0.027	DNM1L
response to unfolded protein	2	25.1×	0.027	MFN2, HSPB1
actin cytoskeleton organization	3	9.9×	0.030	TRPV4, FGD4, SEPTIN9
cellular hypotonic salinity response	1	234.1×	0.033	TRPV4
positive regulation of macrophage inflammatory protein 1 alpha production	1	234.1×	0.033	TRPV4
regulation of peroxisome organization	1	234.1×	0.033	DNM1L
neuron development	2	21.3×	0.033	FIG4, MTMR2
septin cytoskeleton organization	1	175.5×	0.041	SEPTIN9
mitochondrial protein quality control	1	175.5×	0.041	AFG1L
UDP biosynthetic process	1	140.4×	0.041	AK9

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 2 · Phased (≥1): 4 · Undrugged: 22

Druggability breadth: 11 of 26 evidence-associated genes (42%) 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
SEPTIN9	BARICITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TRPV4	6	3
SEPTIN9	3	4
DYNC1H1	1	2
HSPB1	1	2
PRX	0	0
PRDX6	0	0
SBF1	0	0
CCN4	0	0
GDAP1	0	0
AFG1L	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BARICITINIB	4	SEPTIN9
CANNABINOL	3	TRPV4
TETRAHYDROCANNABIVARIN	2	TRPV4
CANNABIDIVARIN	2	TRPV4
GSK2798745	2	TRPV4
CANNABIGEROL	2	TRPV4
MOLIBRESIB	2	DYNC1H1
DORAMAPIMOD	2	HSPB1
TANDUTINIB	2	SEPTIN9
UCN-01	2	SEPTIN9
ABT-102	1	TRPV4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 5.

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

Symbol	Assays	Type breakdown
TRPV4	99	Binding:94, Functional:5
HSPB1	70	Binding:70
PRDX6	15	Binding:15
PLD3	13	Binding:13
DYNC1H1	7	Binding:7
DNM1L	4	Binding:4
NDRG1	4	Binding:4
MFN2	3	Binding:3
PHF20L1	2	Binding:2
SEPTIN9	2	Binding:2
KIF1B	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PRDX6	1.11.1.27, 2.3.1.23, 3.1.1.4	glutathione-dependent peroxiredoxin, 1-acylglycerophosphocholine O-acyltransferase, phospholipase A2
SBF1	3.1.3.16	protein-serine/threonine phosphatase
DNM1L	3.6.5.5	dynamin GTPase
IGHMBP2	3.6.4.12	DNA helicase
MTMR2	3.1.3.64, 3.1.3.95	phosphatidylinositol-3-phosphatase, phosphatidylinositol-3,5-bisphosphate 3-phosphatase

Pharmacogenomics

Cohort genes with a PharmGKB record: 25; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

11 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)
BARICITINIB	4	SEPTIN9
CANNABINOL	3	TRPV4
TETRAHYDROCANNABIVARIN	2	TRPV4
CANNABIDIVARIN	2	TRPV4
GSK2798745	2	TRPV4
CANNABIGEROL	2	TRPV4
MOLIBRESIB	2	DYNC1H1
DORAMAPIMOD	2	HSPB1
TANDUTINIB	2	SEPTIN9
UCN-01	2	SEPTIN9
ABT-102	1	TRPV4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SEPTIN9
B	Phased (≥1) drug, not yet approved	3	TRPV4, DYNC1H1, HSPB1
C	Druggable family + PDB, no drug	3	PRDX6, DNM1L, MTMR2
D	Druggable family + AlphaFold only, no drug	2	SBF1, SBF2
E	Difficult family or no structure, no drug	17	PRX, CCN4, GDAP1, AFG1L, KIF1B, FIG4, MFN2, PLD3, FGD4, MORC2 (+7 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PRX	0	—
PRDX6	15	—
SBF1	0	—
CCN4	0	—
GDAP1	0	—
AFG1L	0	—
KIF1B	1	—
FIG4	0	—
MFN2	3	—
PLD3	13	—
FGD4	0	—
SBF2	0	—
MORC2	0	—
PHF20L1	2	—
LRSAM1	0	—
SBF2-AS1	0	—
SH3TC2	0	—
DNM1L	4	—
AK9	0	—
IGHMBP2	0	—
MTMR2	0	—
NDRG1	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: PRX, PRDX6, SBF1, CCN4, GDAP1, AFG1L, KIF1B, FIG4, MFN2, PLD3, TRPV4, FGD4, SBF2, MORC2, PHF20L1, LRSAM1, SBF2-AS1, SH3TC2, DYNC1H1, DNM1L, AK9, HSPB1, IGHMBP2, SEPTIN9, MTMR2, NDRG1