Hereditary peripheral neuropathy

Summary

Hereditary peripheral neuropathy (MONDO:0020127) is a disease (an umbrella term covering 65 Mondo subtypes) caused by variants in IGHMBP2, PLEKHG5, SARS1, and 1 other genes, with 10 cohort genes and 1 clinical trial. The dominant Reactome pathway is RHOA GTPase cycle (3 cohort genes).

At a glance

• Prevalence: 1-5 / 10 000 (Worldwide)
• Causal genes: IGHMBP2 (GenCC Strong), PLEKHG5 (GenCC Strong), SARS1 (GenCC Strong), SCN9A (GenCC Strong)
• Umbrella term: 65 Mondo subtypes
• Cohort genes: 10
• ClinVar variants: 2
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	40	Worldwide	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary peripheral neuropathy
Mondo ID	MONDO:0020127
Orphanet	98497
UMLS	C5681733
MedGen	1825937
GARD	0010711
Is cancer (heuristic)	no

Also known as: genetic peripheral neuropathy

Data availability: 2 ClinVar variants · 9 GenCC gene-disease records.

Disease family

An umbrella term covering 65 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

Related subtypes (29): autoimmune neuropathy, autonomic neuropathy, mononeuropathy, ischemic neuropathy, polyneuropathy, neuritis, motor peripheral neuropathy, sensory peripheral neuropathy, uremic neuropathy, nerve compression syndrome, axonal neuropathy, diabetic neuropathy, acquired peripheral neuropathy, neuralgia, peripheral nerve lesion, nerve plexus disorder, traumatic neuropathy, radiation-induced neuropathy, vasculitic neuropathy, chronic idiopathic neuropathy, chemotherapy-induced neuropathy, infectious neuropathy, vitamin deficiency related neuropathy, paraproteinemia-associated neuropathy, neuropathy in cryoglobulinemia, neuropathy in endocrine disorder, sarcoid neuropathy, neuropathy, small fiber, idiopathic small fibers neuropathy

Subtypes (65): 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, Charcot-Marie-Tooth disease, 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

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

2 retrieved; paginated sample, class counts are floors:

2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
533815	NM_001540.5(HSPB1):c.380G>A (p.Arg127Gln)	HSPB1	Uncertain significance	criteria provided, multiple submitters, no conflicts
4531652	NM_006513.4(SARS1):c.1231G>A (p.Gly411Arg)	SARS1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 63 · Orphanet: 20 · 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
IGHMBP2	Strong	Autosomal recessive	hereditary peripheral neuropathy	10
PLEKHG5	Strong	Autosomal recessive	hereditary peripheral neuropathy	7
SARS1	Strong	Autosomal dominant	hereditary peripheral neuropathy	5
SCN9A	Strong	Semidominant	hereditary peripheral neuropathy	16
ARHGEF10	Limited	Autosomal dominant	peripheral neuropathy	5
BANF1	Limited	Autosomal dominant	hereditary peripheral neuropathy	7
IQGAP3	Limited	Autosomal dominant	hereditary peripheral neuropathy
KBTBD13	Limited	Autosomal recessive	hereditary peripheral neuropathy	7
TRPA1	Limited	Autosomal dominant	hereditary peripheral neuropathy	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SARS1	Orphanet:2512	Autosomal recessive primary microcephaly
SARS1	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
SCN9A	Orphanet:306577	Hereditary sodium channelopathy-related small fibers neuropathy
SCN9A	Orphanet:33069	Dravet syndrome
SCN9A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN9A	Orphanet:46348	Paroxysmal extreme pain disorder
SCN9A	Orphanet:88642	Congenital insensitivity to pain-anosmia-neuropathic arthropathy
SCN9A	Orphanet:90026	Primary erythromelalgia
SCN9A	Orphanet:970	Hereditary sensory and autonomic neuropathy type 2
ARHGEF10	Orphanet:140481	Autosomal dominant slowed nerve conduction velocity
BANF1	Orphanet:280576	Nestor-Guillermo progeria syndrome
PLEKHG5	Orphanet:206580	Autosomal recessive lower motor neuron disease with childhood onset
PLEKHG5	Orphanet:369867	Autosomal recessive intermediate Charcot-Marie-Tooth disease type C
KBTBD13	Orphanet:171439	Childhood-onset nemaline myopathy
TRPA1	Orphanet:391389	Familial episodic pain syndrome with predominantly upper body involvement
TRPA1	Orphanet:581271	Cramp-fasciculation syndrome
IGHMBP2	Orphanet:443073	Charcot-Marie-Tooth disease type 2S
IGHMBP2	Orphanet:98920	Spinal muscular atrophy with respiratory distress type 1
HSPB1	Orphanet:139525	Distal hereditary motor neuropathy type 2
HSPB1	Orphanet:99940	Autosomal dominant Charcot-Marie-Tooth disease type 2F

Cohort genes → proteins

10 cohort genes, 10 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SARS1	HGNC:10537	ENSG00000031698	P49591	Serine–tRNA ligase, cytoplasmic	gencc,clinvar
SCN9A	HGNC:10597	ENSG00000169432	Q15858	Sodium channel protein type 9 subunit alpha	gencc
ARHGEF10	HGNC:14103	ENSG00000104728	O15013	Rho guanine nucleotide exchange factor 10	gencc
BANF1	HGNC:17397	ENSG00000175334	O75531	Barrier-to-autointegration factor	gencc
IQGAP3	HGNC:20669	ENSG00000183856	Q86VI3	Ras GTPase-activating-like protein IQGAP3	gencc
PLEKHG5	HGNC:29105	ENSG00000171680	O94827	Pleckstrin homology domain-containing family G member 5	gencc
KBTBD13	HGNC:37227	ENSG00000234438	C9JR72	Kelch repeat and BTB domain-containing protein 13	gencc
TRPA1	HGNC:497	ENSG00000104321	O75762	Transient receptor potential cation channel subfamily A member 1	gencc
IGHMBP2	HGNC:5542	ENSG00000132740	P38935	DNA-binding protein SMUBP-2	gencc
HSPB1	HGNC:5246	ENSG00000106211	P04792	Heat shock protein beta-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SARS1	Serine–tRNA ligase, cytoplasmic	Catalyzes the attachment of serine to tRNA(Ser) in a two-step reaction: serine is first activated by ATP to form Ser-AMP and then transferred to the acceptor end of tRNA(Ser).
SCN9A	Sodium channel protein type 9 subunit alpha	Pore-forming subunit of Nav1.7, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
ARHGEF10	Rho guanine nucleotide exchange factor 10	May play a role in developmental myelination of peripheral nerves.
BANF1	Barrier-to-autointegration factor	Non-specific DNA-binding protein that plays key roles in mitotic nuclear reassembly, chromatin organization, DNA damage response, gene expression and intrinsic immunity against foreign DNA.
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.
KBTBD13	Kelch repeat and BTB domain-containing protein 13	Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex.
TRPA1	Transient receptor potential cation channel subfamily A member 1	Ligand-activated Ca(2+)-permeable, nonselective cation channel involved in pain detection and possibly also in cold perception, oxygen concentration perception, cough, itch, and inner ear function.
IGHMBP2	DNA-binding protein SMUBP-2	5’ to 3’ helicase that unwinds RNA and DNA duplexes in an ATP-dependent reaction.
HSPB1	Heat shock protein beta-1	Small heat shock protein which functions as a molecular chaperone probably maintaining denatured proteins in a folding-competent state.

Protein-family classification

Druggable: 3 · Difficult: 3 · Unknown: 4 · Druggable fraction: 0.3

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	22.3×	0.017
Scaffold/PPI	2	3.5×	0.276
Enzyme (other)	1	1.2×	0.906
Transcription factor	1	0.8×	0.906
Other/Unknown	4	0.7×	0.907

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SARS1	Enzyme (other)	yes	6.1.1.11	aa-tRNA-synt_IIb, Ser-tRNA-ligase_type_1, aa-tRNA-synth_II
SCN9A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
ARHGEF10	Scaffold/PPI	no		DH_dom, WD40/YVTN_repeat-like_dom_sf, DBL_dom_sf
BANF1	Other/Unknown	no		BAF_prot, BAF_sf, BAF
IQGAP3	Other/Unknown	no		IQ_motif_EF-hand-BS, IQGAP_helical, CH_dom
PLEKHG5	Scaffold/PPI	no		DH_dom, PH_domain, PH-like_dom_sf
KBTBD13	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf
TRPA1	Ion channel	yes		Ankyrin_rpt, Ion_trans_dom, Ankyrin_rpt-contain_sf
IGHMBP2	Transcription factor	no	3.6.4.12	Znf_AN1, R3H_dom, AAA+_ATPase
HSPB1	Other/Unknown	no		Alpha-crystallin/sHSP_animal, A-crystallin/Hsp20_dom, HSP20-like_chaperone

Expression context

Cohort genes with no expression data: 0.

5 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)	10
unknown	0

Top tissues across cohort

Tissue	Cohort genes
sural nerve	3
oocyte	2
secondary oocyte	2
body of pancreas	1
frontal pole	1
islet of Langerhans	1
dorsal root ganglion	1
stromal cell of endometrium	1
right lung	1
tibial nerve	1
ganglionic eminence	1
right uterine tube	1
ventricular zone	1
buccal mucosa cell	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
hindlimb stylopod muscle	1
primordial germ cell in gonad	1
skeletal muscle tissue	1
mucosa of urinary bladder	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SARS1	291	ubiquitous	marker	islet of Langerhans, body of pancreas, frontal pole
SCN9A	187	ubiquitous	marker	sural nerve, dorsal root ganglion, stromal cell of endometrium
ARHGEF10	134	ubiquitous	yes	sural nerve, tibial nerve, right lung
BANF1	282	ubiquitous	marker	ganglionic eminence, ventricular zone, right uterine tube
IQGAP3	180	ubiquitous	marker	buccal mucosa cell, oocyte, secondary oocyte
PLEKHG5	175	ubiquitous	yes	sural nerve, right hemisphere of cerebellum, cerebellar hemisphere
KBTBD13	47	tissue_specific	yes	primordial germ cell in gonad, hindlimb stylopod muscle, skeletal muscle tissue
TRPA1	167	broad	yes	oocyte, secondary oocyte, mucosa of urinary bladder
IGHMBP2	189	ubiquitous	yes	mucosa of stomach, esophagogastric junction muscularis propria, lower esophagus muscularis layer
HSPB1	299	ubiquitous	marker	lower esophagus mucosa, ascending aorta, thoracic aorta

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HSPB1	5,491
BANF1	3,376
TRPA1	2,451
SARS1	2,306
IQGAP3	2,220
SCN9A	1,575
IGHMBP2	1,265
ARHGEF10	1,071
PLEKHG5	966
KBTBD13	606

Intra-cohort edges

A	B	Sources
HSPB1	SARS1	biogrid_interaction
IGHMBP2	PLEKHG5	string_interaction
SCN9A	TRPA1	string_interaction

Structural data

PDB: 7 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCN9A	Q15858	43
BANF1	O75531	29
TRPA1	O75762	17
SARS1	P49591	9
HSPB1	P04792	6
IGHMBP2	P38935	4
IQGAP3	Q86VI3	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KBTBD13	C9JR72	90.56
ARHGEF10	O15013	65.56
PLEKHG5	O94827	64.94

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 79. Enrichment computed across 10 evidence-associated genes (9 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 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RHOA GTPase cycle	3	24.9×	0.015	ARHGEF10, IQGAP3, PLEKHG5
Integration of viral DNA into host genomic DNA	1	423.0×	0.027	BANF1
Autointegration results in viral DNA circles	1	423.0×	0.027	BANF1
NRAGE signals death through JNK	2	40.9×	0.027	ARHGEF10, PLEKHG5
RHOB GTPase cycle	2	34.3×	0.027	ARHGEF10, IQGAP3
RHOC GTPase cycle	2	32.5×	0.027	ARHGEF10, IQGAP3
G alpha (12/13) signalling events	2	30.6×	0.027	ARHGEF10, PLEKHG5
Integration of provirus	1	253.8×	0.035	BANF1
APOBEC3G mediated resistance to HIV-1 infection	1	253.8×	0.035	BANF1
Early Phase of HIV Life Cycle	1	181.3×	0.039	BANF1
2-LTR circle formation	1	181.3×	0.039	BANF1
Interactions of Vpr with host cellular proteins	1	158.6×	0.039	BANF1
CDC42 GTPase cycle	2	16.1×	0.039	ARHGEF10, IQGAP3
RAC1 GTPase cycle	2	13.6×	0.048	ARHGEF10, IQGAP3
RHO GTPase cycle	2	13.4×	0.048	ARHGEF10, IQGAP3
Initiation of Nuclear Envelope (NE) Reformation	1	66.8×	0.071	BANF1
Nuclear Envelope Breakdown	1	50.8×	0.071	BANF1
Cytosolic tRNA aminoacylation	1	48.8×	0.071	SARS1
TRP channels	1	45.3×	0.071	TRPA1
Attenuation phase	1	45.3×	0.071	HSPB1
HSF1 activation	1	42.3×	0.071	HSPB1
Interaction between L1 and Ankyrins	1	40.9×	0.071	SCN9A
Mitotic Prophase	1	40.9×	0.071	BANF1
Phase 0 - rapid depolarisation	1	38.5×	0.071	SCN9A
RHO GTPases activate IQGAPs	1	38.5×	0.071	IQGAP3
Host Interactions of HIV factors	1	37.3×	0.071	BANF1
Vpr-mediated nuclear import of PICs	1	37.3×	0.071	BANF1
Sensory perception of taste	1	37.3×	0.071	SCN9A
HSF1-dependent transactivation	1	35.2×	0.071	HSPB1
Signaling by Rho GTPases	2	7.6×	0.071	ARHGEF10, IQGAP3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cellular response to food	1	1872.4×	0.008	TRPA1
negative regulation of protein kinase C signaling	1	1872.4×	0.008	HSPB1
action potential propagation	1	1872.4×	0.008	SCN9A
regulation of blood circulation	1	1872.4×	0.008	TRPA1
positive regulation of monoatomic anion transport	1	1872.4×	0.008	TRPA1
negative regulation of vascular endothelial growth factor production	1	1872.4×	0.008	SARS1
sensory perception of pain	2	83.2×	0.008	SCN9A, TRPA1
seryl-tRNA aminoacylation	1	936.2×	0.011	SARS1
negative regulation of protein ADP-ribosylation	1	936.2×	0.011	BANF1
cellular response to carbon dioxide	1	936.2×	0.011	TRPA1
regulation of the force of skeletal muscle contraction	1	624.1×	0.011	KBTBD13
relaxation of skeletal muscle	1	624.1×	0.011	KBTBD13
mitotic actomyosin contractile ring assembly actin filament organization	1	624.1×	0.011	IQGAP3
response to virus	2	32.0×	0.011	BANF1, HSPB1
regulation of small GTPase mediated signal transduction	2	32.0×	0.011	ARHGEF10, PLEKHG5
thermoception	1	468.1×	0.012	TRPA1
detection of chemical stimulus involved in sensory perception of pain	1	468.1×	0.012	TRPA1
regulation of neuronal action potential	1	468.1×	0.012	TRPA1
urinary bladder smooth muscle contraction	1	312.1×	0.016	TRPA1
positive regulation of mammary gland epithelial cell proliferation	1	312.1×	0.016	IQGAP3
detection of mechanical stimulus involved in sensory perception	1	312.1×	0.016	SCN9A
DNA integration	1	234.1×	0.019	BANF1
anterograde axonal protein transport	1	234.1×	0.019	HSPB1
selenocysteine incorporation	1	208.1×	0.020	SARS1
intestinal epithelial structure maintenance	1	208.1×	0.020	HSPB1
mitotic nuclear membrane reassembly	1	187.2×	0.020	BANF1
endothelial cell chemotaxis	1	187.2×	0.020	PLEKHG5
mammary gland epithelial cell proliferation	1	170.2×	0.020	IQGAP3
cellular response to caffeine	1	170.2×	0.020	TRPA1
calcium ion transmembrane import into cytosol	1	170.2×	0.020	TRPA1

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 3 · Undrugged: 7

Druggability breadth: 5 of 10 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
SCN9A	IMIPRAMINE
TRPA1	DICLOFENAC

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN9A	36	4
TRPA1	23	4
HSPB1	1	2
SARS1	0	0
ARHGEF10	0	0
BANF1	0	0
IQGAP3	0	0
PLEKHG5	0	0
KBTBD13	0	0
IGHMBP2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IMIPRAMINE	4	SCN9A
SERTINDOLE	4	SCN9A
PIMOZIDE	4	SCN9A
NIFEDIPINE	4	SCN9A
DILTIAZEM	4	SCN9A
MIBEFRADIL	4	SCN9A
HALOPERIDOL	4	SCN9A
MEXILETINE	4	SCN9A
AMITRIPTYLINE	4	SCN9A
AMIODARONE	4	SCN9A
CHLORPROMAZINE	4	SCN9A
CARBAMAZEPINE	4	SCN9A
MEXILETINE HYDROCHLORIDE	4	SCN9A
CANNABIDIOL	4	SCN9A
SAFINAMIDE	4	SCN9A
LACOSAMIDE	4	SCN9A
TETRACAINE	4	SCN9A
LAMOTRIGINE	4	SCN9A
RILUZOLE	4	SCN9A
LIDOCAINE	4	SCN9A
DICLOFENAC	4	TRPA1
MENTHOL	4	TRPA1
NICOTINE	4	TRPA1
MEFENAMIC ACID	4	TRPA1
DISULFIRAM	4	TRPA1
TEDISAMIL	3	SCN9A
NITRENDIPINE	3	SCN9A
AJMALINE	3	SCN9A
RALFINAMIDE	3	SCN9A
VIXOTRIGINE	3	SCN9A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
SCN9A	428	Binding:395, Functional:29, ADMET:3, Toxicity:1
TRPA1	344	Binding:289, Functional:49, ADMET:6
HSPB1	70	Binding:70
SARS1	2	ADMET:1, Binding:1
BANF1	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SARS1	6.1.1.11	serine-tRNA ligase
IGHMBP2	3.6.4.12	DNA helicase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN9A	428
TRPA1	344

Pharmacogenomics

Cohort genes with a PharmGKB record: 10; 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)
IMIPRAMINE	4	SCN9A
SERTINDOLE	4	SCN9A
PIMOZIDE	4	SCN9A
NIFEDIPINE	4	SCN9A
DILTIAZEM	4	SCN9A
MIBEFRADIL	4	SCN9A
HALOPERIDOL	4	SCN9A
MEXILETINE	4	SCN9A
AMITRIPTYLINE	4	SCN9A
AMIODARONE	4	SCN9A
CHLORPROMAZINE	4	SCN9A
CARBAMAZEPINE	4	SCN9A
MEXILETINE HYDROCHLORIDE	4	SCN9A
CANNABIDIOL	4	SCN9A
SAFINAMIDE	4	SCN9A
LACOSAMIDE	4	SCN9A
TETRACAINE	4	SCN9A
LAMOTRIGINE	4	SCN9A
RILUZOLE	4	SCN9A
LIDOCAINE	4	SCN9A
DICLOFENAC	4	TRPA1
MENTHOL	4	TRPA1
NICOTINE	4	TRPA1
MEFENAMIC ACID	4	TRPA1
DISULFIRAM	4	TRPA1
TEDISAMIL	3	SCN9A
NITRENDIPINE	3	SCN9A
AJMALINE	3	SCN9A
RALFINAMIDE	3	SCN9A
VIXOTRIGINE	3	SCN9A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	SCN9A, TRPA1
B	Phased (≥1) drug, not yet approved	1	HSPB1
C	Druggable family + PDB, no drug	1	SARS1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	6	ARHGEF10, BANF1, IQGAP3, PLEKHG5, KBTBD13, IGHMBP2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SARS1	2	—
ARHGEF10	0	—
BANF1	2	—
IQGAP3	0	—
PLEKHG5	0	—
KBTBD13	0	—
IGHMBP2	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
NCT03278093	Not specified	UNKNOWN	Effect of Orthoses and Underfoot Vibration on Balance in Neuropathy