Hereditary motor neuron disease

Summary

Hereditary motor neuron disease (MONDO:0024257) is a disease (an umbrella term covering 9 Mondo subtypes) with 12 cohort genes.

At a glance

• Umbrella term: 9 Mondo subtypes
• Cohort genes: 12
• ClinVar variants: 14

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary motor neuron disease
Mondo ID	MONDO:0024257
Orphanet	98505
SNOMED CT	49793008
UMLS	C0270763
MedGen	78728
GARD	0019478
Is cancer (heuristic)	no

Also known as: genetic anterior horn cell disease · genetic motor neuron disease · hereditary motor neuron disease

Data availability: 14 ClinVar variants.

Disease family

An umbrella term covering 9 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › motor neuron disorder › hereditary motor neuron disease

Related subtypes (3): amyotrophic lateral sclerosis, Madras motor neuron disease, acquired motor neuron disease

Subtypes (9): prenatal-onset spinal muscular atrophy with congenital bone fractures, spinal muscular atrophy, familial amyotrophic lateral sclerosis, neurogenic scapuloperoneal syndrome, Kaeser type, riboflavin transporter deficiency, motor neuron disease with dementia and ophthalmoplegia, lateral sclerosis, distal hereditary motor neuropathy, ALS2-related motor neuron disease

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

14 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 4 conflicting classifications of pathogenicity, 3 pathogenic, 1 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
565763	NM_004082.5(DCTN1):c.279+1G>T	DCTN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8401	NM_004082.5(DCTN1):c.175G>A (p.Gly59Ser)	DCTN1	Pathogenic	criteria provided, single submitter
567011	NM_014874.4(MFN2):c.475-2A>G	MFN2	Pathogenic	criteria provided, single submitter
5002	NM_021625.5(TRPV4):c.805C>T (p.Arg269Cys)	TRPV4	Pathogenic	criteria provided, multiple submitters, no conflicts
447763	NM_006158.5(NEFL):c.793T>G (p.Tyr265Asp)	NEFL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1019	NM_020631.6(PLEKHG5):c.1940T>C (p.Phe647Ser)	PLEKHG5	Conflicting classifications of pathogenicity	no assertion criteria provided
474743	NM_001349253.2(SCN11A):c.5067C>G (p.Phe1689Leu)	SCN11A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
452652	NM_024577.4(SH3TC2):c.1325C>T (p.Pro442Leu)	SH3TC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
637077	NM_001376.5(DYNC1H1):c.3179T>C (p.Leu1060Ser)	DYNC1H1	Uncertain significance	no assertion criteria provided
637107	NM_002047.4(GARS1):c.998A>G (p.Glu333Gly)	GARS1	Uncertain significance	no assertion criteria provided
581604	NM_000530.8(MPZ):c.268G>A (p.Asp90Asn)	MPZ	Uncertain significance	criteria provided, single submitter
4072159	NM_012123.4(MTO1):c.1260+187T>G	MTO1	Uncertain significance	criteria provided, single submitter
637405	NM_015046.7(SETX):c.6052A>G (p.Lys2018Glu)	SETX	Uncertain significance	no assertion criteria provided
637068	NM_004082.5(DCTN1):c.2054T>G (p.Val685Gly)	DCTN1	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 45 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
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
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
MTO1	Orphanet:314637	Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency
DCTN1	Orphanet:139589	Distal hereditary motor neuropathy type 7
DCTN1	Orphanet:178509	Perry syndrome
DCTN1	Orphanet:803	Amyotrophic lateral sclerosis
PLEKHG5	Orphanet:206580	Autosomal recessive lower motor neuron disease with childhood onset
PLEKHG5	Orphanet:369867	Autosomal recessive intermediate Charcot-Marie-Tooth disease type C
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
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
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

Cohort genes → proteins

12 cohort genes, 12 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	12

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCN11A	HGNC:10583	ENSG00000168356	Q9UI33	Sodium channel protein type 11 subunit alpha	clinvar
MFN2	HGNC:16877	ENSG00000116688	O95140	Mitofusin-2	clinvar
TRPV4	HGNC:18083	ENSG00000111199	Q9HBA0	Transient receptor potential cation channel subfamily V member 4	clinvar
MTO1	HGNC:19261	ENSG00000135297	Q9Y2Z2	5-taurinomethyluridine-[tRNA] synthase subunit MTO1, mitochondrial	clinvar
DCTN1	HGNC:2711	ENSG00000204843	Q14203	Dynactin subunit 1	clinvar
PLEKHG5	HGNC:29105	ENSG00000171680	O94827	Pleckstrin homology domain-containing family G member 5	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
GARS1	HGNC:4162	ENSG00000106105	P41250	Glycine–tRNA ligase	clinvar
SETX	HGNC:445	ENSG00000107290	Q7Z333	Helicase senataxin	clinvar
MPZ	HGNC:7225	ENSG00000158887	P25189	Myelin protein P0	clinvar
NEFL	HGNC:7739	ENSG00000277586	P07196	Neurofilament light polypeptide	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCN11A	Sodium channel protein type 11 subunit alpha	Sodium channel mediating the voltage-dependent sodium ion permeability of excitable membranes.
MFN2	Mitofusin-2	Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion.
TRPV4	Transient receptor potential cation channel subfamily V member 4	Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity.
MTO1	5-taurinomethyluridine-[tRNA] synthase subunit MTO1, mitochondrial	Component of the GTPBP3-MTO1 complex that catalyzes the 5-taurinomethyluridine (taum(5)U) modification at the 34th wobble position (U34) of mitochondrial tRNAs (mt-tRNAs), which plays a role in mt-tRNA decoding and mitochondrial translatio…
DCTN1	Dynactin subunit 1	Part of the dynactin complex that activates the molecular motor dynein for ultra-processive transport along microtubules.
PLEKHG5	Pleckstrin homology domain-containing family G member 5	Functions as a guanine exchange factor (GEF) for RAB26 and thus regulates autophagy of synaptic vesicles in axon terminal of motoneurons.
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.
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.
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.

Protein-family classification

Druggable: 4 · Difficult: 2 · Unknown: 6 · Druggable fraction: 0.33

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
Ion channel	2	18.6×	0.025
Scaffold/PPI	2	2.9×	0.376
Antibody/Immunoglobulin	1	2.4×	0.570
Enzyme (other)	1	1.0×	0.758
Other/Unknown	6	0.9×	0.758

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN11A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_trans_assoc_dom
MFN2	Other/Unknown	no		Fzo/mitofusin_HR2, Mitofusin_fam, P-loop_NTPase
TRPV4	Ion channel	yes		Ankyrin_rpt, Ion_trans_dom, TrpV1-4
MTO1	Other/Unknown	no		MnmG-rel, MnmG-rel_CS, MnmG_C
DCTN1	Other/Unknown	no		CAP-Gly_domain, Dynactin, CAP-Gly_dom_sf
PLEKHG5	Scaffold/PPI	no		DH_dom, PH_domain, PH-like_dom_sf
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
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
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

Expression context

Cohort genes with no expression data: 0.

11 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)	12
unknown	0

Top tissues across cohort

Tissue	Cohort genes
sural nerve	3
dorsal root ganglion	2
cartilage tissue	2
right hemisphere of cerebellum	2
lateral nuclear group of thalamus	2
buccal mucosa cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
apex of heart	1
cardiac ventricle	1
heart left ventricle	1
lower esophagus mucosa	1
olfactory segment of nasal mucosa	1
endothelial cell	1
germinal epithelium of ovary	1
sperm	1
prefrontal cortex	1
right frontal lobe	1
cerebellar hemisphere	1
C1 segment of cervical spinal cord	1
corpus callosum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCN11A	166	broad	marker	buccal mucosa cell, dorsal root ganglion, male germ line stem cell (sensu Vertebrata) in testis
MFN2	297	ubiquitous	marker	apex of heart, heart left ventricle, cardiac ventricle
TRPV4	171	ubiquitous	marker	cartilage tissue, lower esophagus mucosa, olfactory segment of nasal mucosa
MTO1	284	ubiquitous	marker	germinal epithelium of ovary, sperm, endothelial cell
DCTN1	275	ubiquitous	marker	right frontal lobe, prefrontal cortex, right hemisphere of cerebellum
PLEKHG5	175	ubiquitous	yes	sural nerve, right hemisphere of cerebellum, cerebellar hemisphere
SH3TC2	168	broad	marker	corpus callosum, sural nerve, C1 segment of cervical spinal cord
DYNC1H1	290	ubiquitous	marker	cortical plate, ganglionic eminence, 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
MPZ	178	ubiquitous	marker	tibial nerve, sural nerve, olfactory bulb
NEFL	214	broad	marker	dorsal root ganglion, pons, lateral nuclear group of thalamus

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NEFL	4,644
DYNC1H1	4,215
MFN2	3,853
DCTN1	3,654
SETX	3,127
GARS1	2,426
MTO1	2,309
TRPV4	1,948
SCN11A	1,202
PLEKHG5	966

Intra-cohort edges

A	B	Sources
DCTN1	DYNC1H1	biogrid_interaction, string_interaction
DCTN1	SETX	string_interaction
PLEKHG5	SH3TC2	string_interaction

Structural data

PDB: 6 · AlphaFold-only: 6 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DYNC1H1	Q14204	97
TRPV4	Q9HBA0	19
GARS1	P41250	14
DCTN1	Q14203	13
MFN2	O95140	3
MPZ	P25189	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MTO1	Q9Y2Z2	85.95
SH3TC2	Q8TF17	78.63
NEFL	P07196	73.66
SCN11A	Q9UI33	69.66
PLEKHG5	O94827	64.94
SETX	Q7Z333	52.93

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 60. Enrichment computed across 12 evidence-associated genes (10 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 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
COPI-independent Golgi-to-ER retrograde traffic	2	41.5×	0.021	DCTN1, DYNC1H1
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	2	38.7×	0.021	DCTN1, DYNC1H1
Loss of Nlp from mitotic centrosomes	2	31.7×	0.021	DCTN1, DYNC1H1
Loss of proteins required for interphase microtubule organization from the centrosome	2	31.7×	0.021	DCTN1, DYNC1H1
AURKA Activation by TPX2	2	30.4×	0.021	DCTN1, DYNC1H1
Recruitment of mitotic centrosome proteins and complexes	2	27.2×	0.021	DCTN1, DYNC1H1
Regulation of PLK1 Activity at G2/M Transition	2	25.4×	0.021	DCTN1, DYNC1H1
Recruitment of NuMA to mitotic centrosomes	2	23.3×	0.021	DCTN1, DYNC1H1
Anchoring of the basal body to the plasma membrane	2	22.6×	0.021	DCTN1, DYNC1H1
COPI-mediated anterograde transport	2	22.0×	0.021	DCTN1, DYNC1H1
Miro GTPase Cycle	1	228.4×	0.024	MFN2
MHC class II antigen presentation	2	17.8×	0.026	DCTN1, DYNC1H1
RHOT2 GTPase cycle	1	163.1×	0.028	MFN2
Mitophagy	1	103.8×	0.038	MFN2
tRNA modification in the mitochondrion	1	103.8×	0.038	MTO1
Ras activation upon Ca2+ influx through NMDA receptor	1	57.1×	0.060	NEFL
Unblocking of NMDA receptors, glutamate binding and activation	1	54.4×	0.060	NEFL
Negative regulation of NMDA receptor-mediated neuronal transmission	1	54.4×	0.060	NEFL
Mitochondrial tRNA aminoacylation	1	51.9×	0.060	GARS1
Long-term potentiation	1	47.6×	0.061	NEFL
Cytosolic tRNA aminoacylation	1	43.9×	0.061	GARS1
TRP channels	1	40.8×	0.061	TRPV4
Interaction between L1 and Ankyrins	1	36.8×	0.061	SCN11A
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	36.8×	0.061	MPZ
PINK1-PRKN Mediated Mitophagy	1	35.7×	0.061	MFN2
tRNA processing	1	35.7×	0.061	MTO1
Phase 0 - rapid depolarisation	1	34.6×	0.061	SCN11A
Nervous system development	2	8.6×	0.061	SCN11A, MPZ
Selective autophagy	1	27.9×	0.072	MFN2
RND1 GTPase cycle	1	26.6×	0.072	PLEKHG5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 12 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
retrograde axonal transport	2	255.3×	0.005	DYNC1H1, NEFL
regulation of mitotic spindle organization	2	140.4×	0.007	DCTN1, DYNC1H1
nuclear migration	2	122.1×	0.007	DCTN1, DYNC1H1
hyperosmotic salinity response	1	1404.3×	0.011	TRPV4
intermediate filament polymerization or depolymerization	1	1404.3×	0.011	NEFL
reflex	1	1404.3×	0.011	SCN11A
positive regulation of termination of DNA-templated transcription	1	1404.3×	0.011	SETX
blood vessel endothelial cell delamination	1	1404.3×	0.011	TRPV4
regulation of ERBB signaling pathway	1	1404.3×	0.011	SH3TC2
small intestine smooth muscle contraction	1	1404.3×	0.011	SCN11A
vasopressin secretion	1	702.2×	0.011	TRPV4
thermosensory behavior	1	702.2×	0.011	SCN11A
positive regulation of striated muscle contraction	1	702.2×	0.011	TRPV4
regulation of response to osmotic stress	1	702.2×	0.011	TRPV4
behavioral response to acetic acid induced pain	1	702.2×	0.011	SCN11A
mitochondrial glycyl-tRNA aminoacylation	1	702.2×	0.011	GARS1
mitochondrial tRNA wobble uridine modification	1	702.2×	0.011	MTO1
cell aggregation	1	702.2×	0.011	MPZ
calcium ion import into cytosol	1	702.2×	0.011	TRPV4
response to sodium arsenite	1	702.2×	0.011	NEFL
response to acrylamide	1	702.2×	0.011	NEFL
positive regulation of neuromuscular junction development	1	702.2×	0.011	DCTN1
circadian rhythm	2	40.7×	0.011	SCN11A, SETX
response to toxic substance	2	35.1×	0.011	SCN11A, NEFL
calcium ion transmembrane transport	2	35.1×	0.011	SCN11A, TRPV4
response to high light intensity	1	468.1×	0.012	SCN11A
diadenosine tetraphosphate biosynthetic process	1	468.1×	0.012	GARS1
neurofilament bundle assembly	1	468.1×	0.012	NEFL
micturition	1	468.1×	0.012	SCN11A
behavioral response to formalin induced pain	1	468.1×	0.012	SCN11A

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 3 · Phased (≥1): 4 · Undrugged: 8

Druggability breadth: 6 of 12 evidence-associated genes (50%) 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
SCN11A	IMIPRAMINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN11A	15	4
TRPV4	6	3
DYNC1H1	1	2
GARS1	1	3
MFN2	0	0
MTO1	0	0
DCTN1	0	0
PLEKHG5	0	0
SH3TC2	0	0
SETX	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
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
TEDISAMIL	3	SCN11A
NITRENDIPINE	3	SCN11A
AJMALINE	3	SCN11A
CANNABINOL	3	TRPV4
CRENOLANIB	3	GARS1
CIFENLINE	2	SCN11A
TETRAHYDROCANNABIVARIN	2	TRPV4
CANNABIDIVARIN	2	TRPV4
GSK2798745	2	TRPV4
CANNABIGEROL	2	TRPV4
MOLIBRESIB	2	DYNC1H1
ABT-102	1	TRPV4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TRPV4	99	Binding:94, Functional:5
SCN11A	33	Functional:16, Binding:15, ADMET:2
GARS1	8	Binding:8
DYNC1H1	7	Binding:7
MFN2	3	Binding:3
DCTN1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GARS1	6.1.1.14	glycine-tRNA ligase

Pharmacogenomics

Cohort genes with a PharmGKB record: 12; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

23 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)
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
TEDISAMIL	3	SCN11A
NITRENDIPINE	3	SCN11A
AJMALINE	3	SCN11A
CANNABINOL	3	TRPV4
CRENOLANIB	3	GARS1
CIFENLINE	2	SCN11A
TETRAHYDROCANNABIVARIN	2	TRPV4
CANNABIDIVARIN	2	TRPV4
GSK2798745	2	TRPV4
CANNABIGEROL	2	TRPV4
MOLIBRESIB	2	DYNC1H1
ABT-102	1	TRPV4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SCN11A
B	Phased (≥1) drug, not yet approved	3	TRPV4, DYNC1H1, GARS1
C	Druggable family + PDB, no drug	1	MPZ
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	7	MFN2, MTO1, DCTN1, PLEKHG5, SH3TC2, SETX, NEFL

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MFN2	3	—
MTO1	0	—
DCTN1	1	—
PLEKHG5	0	—
SH3TC2	0	—
SETX	0	—
MPZ	0	—
NEFL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.