neuropathy, hereditary sensory and autonomic, type 2A

Summary

neuropathy, hereditary sensory and autonomic, type 2A (MONDO:0024309) is a disease caused by WNK1 (GenCC Definitive), with 9 cohort genes. The dominant Reactome pathway is Interaction between L1 and Ankyrins (3 cohort genes).

At a glance

• Causal gene: WNK1 (GenCC Definitive)
• Cohort genes: 9
• ClinVar variants: 4,745

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neuropathy, hereditary sensory and autonomic, type 2A
Mondo ID	MONDO:0024309
OMIM	201300
DOID	DOID:0070155
UMLS	C2752089
MedGen	416701
GARD	0015129
Is cancer (heuristic)	no

Also known as: HSAN 2A · HSAN2A · HSN 2A · Morvan disease · neuropathy, hereditary sensory and autonomic, type II · neuropathy, hereditary sensory and autonomic, type IIA · neuropathy, hereditary sensory, type 2A

Data availability: 4,745 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › sensory peripheral neuropathy › hereditary sensory and autonomic neuropathy › hereditary sensory and autonomic neuropathy type 2 › neuropathy, hereditary sensory and autonomic, type 2A

Related subtypes (2): neuropathy, hereditary sensory and autonomic, type 2B, neuropathy, hereditary sensory, type 2C

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:

303 uncertain significance, 229 likely benign, 28 conflicting classifications of pathogenicity, 16 pathogenic, 13 benign, 6 benign/likely benign, 3 likely pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1054402	NC_000002.11:g.(?165946660)(167168266_?)del	SCN1A	Pathogenic	criteria provided, single submitter
1069309	NM_001365536.1(SCN9A):c.5004T>A (p.Tyr1668Ter)	SCN1A-AS1	Pathogenic	criteria provided, single submitter
1354382	NM_001365536.1(SCN9A):c.1497del (p.Lys499fs)	SCN1A-AS1	Pathogenic	criteria provided, single submitter
1024965	NM_001365536.1(SCN9A):c.2599G>C (p.Gly867Arg)	SCN9A	Pathogenic	criteria provided, single submitter
1068510	NM_001365536.1(SCN9A):c.2204del (p.Lys735fs)	SCN9A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068637	NM_001365536.1(SCN9A):c.5100G>A (p.Trp1700Ter)	SCN9A	Pathogenic	criteria provided, single submitter
1070653	NM_001365536.1(SCN9A):c.2984_2985insC (p.Ile995_Lys996insTer)	SCN9A	Pathogenic	criteria provided, single submitter
1070796	NM_001365536.1(SCN9A):c.4740_4743dup (p.Asp1582delinsPheTer)	SCN9A	Pathogenic	criteria provided, single submitter
1074563	NC_000002.11:g.(?167055172)(167060984_?)del	SCN9A	Pathogenic	criteria provided, single submitter
1075008	NM_001365536.1(SCN9A):c.116del (p.Lys39fs)	SCN9A	Pathogenic	criteria provided, single submitter
1075155	NM_001365536.1(SCN9A):c.4855C>T (p.Arg1619Ter)	SCN9A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075796	NM_001365536.1(SCN9A):c.2667dup (p.Lys890Ter)	SCN9A	Pathogenic	criteria provided, single submitter
1076717	NM_001365536.1(SCN9A):c.2409T>A (p.Tyr803Ter)	SCN9A	Pathogenic	criteria provided, single submitter
1076959	NM_001365536.1(SCN9A):c.3801+1G>A	SCN9A	Pathogenic	criteria provided, single submitter
1355824	NM_001365536.1(SCN9A):c.3183_3199del (p.Phe1062fs)	SCN9A	Pathogenic	criteria provided, single submitter
1069964	NM_213655.5(WNK1):c.2436C>A (p.Tyr812Ter)	WNK1	Pathogenic	criteria provided, single submitter
1071299	NM_213655.5(WNK1):c.2462_2463dup (p.Ile822fs)	WNK1	Pathogenic	criteria provided, single submitter
1075747	NM_213655.5(WNK1):c.3088_3091del (p.Val1030fs)	WNK1	Pathogenic	criteria provided, single submitter
1067970	NM_001365536.1(SCN9A):c.4398+2T>C	SCN1A-AS1	Likely pathogenic	criteria provided, single submitter
1065969	NM_001365536.1(SCN9A):c.2517+1G>C	SCN9A	Likely pathogenic	criteria provided, single submitter
1067284	NM_001365536.1(SCN9A):c.596+1G>T	SCN9A	Likely pathogenic	criteria provided, single submitter
1009584	NM_001244008.2(KIF1A):c.2341G>A (p.Ala781Thr)	KIF1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1040792	NM_001244008.2(KIF1A):c.3465C>T (p.Asn1155=)	KIF1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1197186	NM_001244008.2(KIF1A):c.3609C>A (p.His1203Gln)	KIF1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1338222	NM_001244008.2(KIF1A):c.4750G>A (p.Glu1584Lys)	KIF1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1114593	NM_001365536.1(SCN9A):c.2146A>C (p.Arg716=)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1163420	NM_001365536.1(SCN9A):c.3706A>G (p.Ile1236Val)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
130260	NM_001365536.1(SCN9A):c.3002A>G (p.Tyr1001Cys)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
130263	NM_001365536.1(SCN9A):c.3509T>C (p.Ile1170Thr)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
130265	NM_001365536.1(SCN9A):c.3767A>G (p.Asn1256Ser)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 30 · 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
WNK1	Definitive	Autosomal recessive	neuropathy, hereditary sensory and autonomic, type 2A	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WNK1	Orphanet:88940	Pseudohypoaldosteronism type 2C
WNK1	Orphanet:970	Hereditary sensory and autonomic neuropathy type 2
SCN1A	Orphanet:1942	Epilepsy with myoclonic-atonic seizures
SCN1A	Orphanet:2382	Lennox-Gastaut syndrome
SCN1A	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
SCN1A	Orphanet:33069	Dravet syndrome
SCN1A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN1A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SCN1A	Orphanet:569	Familial or sporadic hemiplegic migraine
SCN2A	Orphanet:140927	Self-limited neonatal-infantile epilepsy
SCN2A	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
SCN2A	Orphanet:2131	Alternating hemiplegia of childhood
SCN2A	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
SCN2A	Orphanet:306	Self-limited infantile epilepsy
SCN2A	Orphanet:33069	Dravet syndrome
SCN2A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN2A	Orphanet:697160	Infantile epileptic spasms syndrome
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
TTC21B	Orphanet:474	Jeune syndrome
TTC21B	Orphanet:93591	Infantile nephronophthisis
RETREG1	Orphanet:970	Hereditary sensory and autonomic neuropathy type 2
KIF1A	Orphanet:101010	Autosomal spastic paraplegia type 30
KIF1A	Orphanet:662367	NESCAV syndrome
KIF1A	Orphanet:970	Hereditary sensory and autonomic neuropathy type 2

Cohort genes → proteins

9 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	9

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
WNK1	HGNC:14540	ENSG00000060237	Q9H4A3	Serine/threonine-protein kinase WNK1	gencc,clinvar
SCN1A	HGNC:10585	ENSG00000144285	P35498	Sodium channel protein type 1 subunit alpha	clinvar
SCN2A	HGNC:10588	ENSG00000136531	Q99250	Sodium channel protein type 2 subunit alpha	clinvar
SCN9A	HGNC:10597	ENSG00000169432	Q15858	Sodium channel protein type 9 subunit alpha	clinvar
TTC21B	HGNC:25660	ENSG00000123607	Q7Z4L5	Tetratricopeptide repeat protein 21B	clinvar
RETREG1	HGNC:25964	ENSG00000154153	Q9H6L5	Reticulophagy regulator 1	clinvar
CSRNP3	HGNC:30729	ENSG00000178662	Q8WYN3	Cysteine/serine-rich nuclear protein 3	clinvar
SCN1A-AS1	HGNC:54069	ENSG00000236107		SCN1A and SCN9A antisense RNA 1	clinvar
KIF1A	HGNC:888	ENSG00000130294	Q12756	Kinesin-like protein KIF1A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WNK1	Serine/threonine-protein kinase WNK1	Serine/threonine-protein kinase component of the WNK1-SPAK/OSR1 kinase cascade, which acts as a key regulator of blood pressure and regulatory volume increase by promoting ion influx.
SCN1A	Sodium channel protein type 1 subunit alpha	Pore-forming subunit of Nav1.1, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
SCN2A	Sodium channel protein type 2 subunit alpha	Mediates the voltage-dependent sodium ion permeability of excitable membranes.
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.
TTC21B	Tetratricopeptide repeat protein 21B	Component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs).
RETREG1	Reticulophagy regulator 1	Endoplasmic reticulum (ER)-anchored autophagy regulator which mediates ER delivery into lysosomes through sequestration into autophagosomes.
CSRNP3	Cysteine/serine-rich nuclear protein 3	Binds to the consensus sequence 5’-AGAGTG-3’ and has transcriptional activator activity.
KIF1A	Kinesin-like protein KIF1A	Kinesin motor with a plus-end-directed microtubule motor activity.

Protein-family classification

Druggable: 4 · Difficult: 1 · Unknown: 4 · Druggable fraction: 0.44

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	3	37.2×	2e-04
Kinase	1	3.1×	0.553
Scaffold/PPI	1	1.9×	0.553
Other/Unknown	4	0.8×	0.847

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
WNK1	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
SCN1A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a1su
SCN2A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
SCN9A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
TTC21B	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, TTC21A/TTC21B
RETREG1	Other/Unknown	no		RETREG1/3, RETR1_RHD, RETREG1-3-like_RHD
CSRNP3	Other/Unknown	no		Cys/Ser-rich_nuc_prot, CSRNP_N
SCN1A-AS1	Other/Unknown	no
KIF1A	Scaffold/PPI	no	5.6.1.3	FHA_dom, Kinesin_motor_dom, PH_domain

Expression context

Cohort genes with no expression data: 0.

9 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)	9
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	3
middle temporal gyrus	2
sural nerve	2
globus pallidus	1
inferior vagus X ganglion	1
medial globus pallidus	1
lateral nuclear group of thalamus	1
primary visual cortex	1
cerebellar vermis	1
dorsal root ganglion	1
stromal cell of endometrium	1
calcaneal tendon	1
cerebellar hemisphere	1
right uterine tube	1
diaphragm	1
heart right ventricle	1
skeletal muscle tissue of rectus abdominis	1
entorhinal cortex	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WNK1	297	ubiquitous	marker	medial globus pallidus, globus pallidus, inferior vagus X ganglion
SCN1A	154	tissue_specific	marker	Brodmann (1909) area 23, lateral nuclear group of thalamus, primary visual cortex
SCN2A	187	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, cerebellar vermis
SCN9A	187	ubiquitous	marker	sural nerve, dorsal root ganglion, stromal cell of endometrium
TTC21B	179	ubiquitous	marker	right uterine tube, calcaneal tendon, cerebellar hemisphere
RETREG1	283	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, diaphragm, heart right ventricle
CSRNP3	226	broad	marker	Brodmann (1909) area 23, middle temporal gyrus, entorhinal cortex
SCN1A-AS1	129	tissue_specific	marker	sural nerve, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
KIF1A	198	broad	marker	right frontal lobe, postcentral gyrus, parietal lobe

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KIF1A	2,833
SCN2A	2,810
SCN1A	2,287
RETREG1	1,899
TTC21B	1,588
SCN9A	1,575
CSRNP3	486
WNK1	371
SCN1A-AS1	0

Intra-cohort edges

A	B	Sources
SCN1A	SCN2A	biogrid_interaction, string_interaction
SCN2A	SCN9A	intact

Structural data

PDB: 7 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCN9A	Q15858	43
KIF1A	Q12756	21
WNK1	Q9H4A3	5
SCN2A	Q99250	5
TTC21B	Q7Z4L5	3
RETREG1	Q9H6L5	2
SCN1A	P35498	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CSRNP3	Q8WYN3	60.42

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. Enrichment computed across 9 evidence-associated genes (7 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 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interaction between L1 and Ankyrins	3	157.9×	9e-06	SCN1A, SCN2A, SCN9A
Phase 0 - rapid depolarisation	3	148.3×	9e-06	SCN1A, SCN2A, SCN9A
L1CAM interactions	3	51.5×	1e-04	SCN1A, SCN2A, SCN9A
Cardiac conduction	3	46.6×	1e-04	SCN1A, SCN2A, SCN9A
Muscle contraction	3	33.1×	3e-04	SCN1A, SCN2A, SCN9A
Sensory perception of taste	2	96.0×	7e-04	SCN2A, SCN9A
Sensory perception of sweet, bitter, and umami (glutamate) taste	2	79.6×	9e-04	SCN2A, SCN9A
Axon guidance	3	19.4×	0.001	SCN1A, SCN2A, SCN9A
Nervous system development	3	18.4×	0.001	SCN1A, SCN2A, SCN9A
Sensory Perception	2	27.2×	0.005	SCN2A, SCN9A
Dengue virus modulates apoptosis	1	102.0×	0.019	RETREG1
Developmental Biology	3	6.2×	0.019	SCN1A, SCN2A, SCN9A
Intraflagellar transport	1	28.6×	0.059	TTC21B
Hedgehog ‘off’ state	1	25.5×	0.059	TTC21B
Kinesins	1	25.5×	0.059	KIF1A
Stimuli-sensing channels	1	19.4×	0.070	WNK1
Golgi-to-ER retrograde transport	1	19.0×	0.070	KIF1A
COPI-dependent Golgi-to-ER retrograde traffic	1	15.8×	0.079	KIF1A
Intra-Golgi and retrograde Golgi-to-ER traffic	1	15.0×	0.079	KIF1A
Factors involved in megakaryocyte development and platelet production	1	9.5×	0.116	KIF1A
Membrane Trafficking	1	5.3×	0.185	KIF1A
Hemostasis	1	5.2×	0.185	KIF1A
Vesicle-mediated transport	1	5.0×	0.185	KIF1A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sodium ion transmembrane transport	4	101.5×	4e-06	WNK1, SCN1A, SCN2A, SCN9A
cardiac muscle cell action potential involved in contraction	3	263.3×	7e-06	SCN1A, SCN2A, SCN9A
neuronal action potential	3	180.6×	1e-05	SCN1A, SCN2A, SCN9A
sensory perception of pain	2	93.6×	0.005	SCN9A, RETREG1
action potential propagation	1	2106.5×	0.006	SCN9A
positive regulation of termination of RNA polymerase II transcription	1	2106.5×	0.006	WNK1
sodium ion transport	2	68.0×	0.006	SCN1A, SCN2A
intrinsic apoptotic signaling pathway in response to osmotic stress	1	1053.2×	0.008	SCN2A
negative regulation of cell-cell adhesion mediated by integrin	1	1053.2×	0.008	WNK1
monoatomic cation homeostasis	1	1053.2×	0.008	WNK1
regulation of intraciliary retrograde transport	1	1053.2×	0.008	TTC21B
positive regulation of canonical Wnt signaling pathway	2	38.6×	0.009	WNK1, TTC21B
chemokine (C-C motif) ligand 21 signaling pathway	1	526.6×	0.010	WNK1
lymphocyte migration into lymph node	1	526.6×	0.010	WNK1
protein localization to non-motile cilium	1	526.6×	0.010	TTC21B
dense core granule cytoskeletal transport	1	526.6×	0.010	KIF1A
anterograde neuronal dense core vesicle transport	1	526.6×	0.010	KIF1A
negative regulation of pancreatic juice secretion	1	421.3×	0.011	WNK1
retrograde neuronal dense core vesicle transport	1	421.3×	0.011	KIF1A
negative regulation of sodium ion transport	1	351.1×	0.011	WNK1
detection of mechanical stimulus involved in sensory perception	1	351.1×	0.011	SCN9A
negative regulation of leukocyte cell-cell adhesion	1	351.1×	0.011	WNK1
positive regulation of mitotic cytokinesis	1	351.1×	0.011	WNK1
negative regulation of eating behavior	1	351.1×	0.011	TTC21B
regulation of mRNA export from nucleus	1	263.3×	0.013	WNK1
forebrain dorsal/ventral pattern formation	1	263.3×	0.013	TTC21B
regulation of monoatomic cation transmembrane transport	1	263.3×	0.013	WNK1
negative regulation of heterotypic cell-cell adhesion	1	234.1×	0.014	WNK1
intracellular chloride ion homeostasis	1	210.7×	0.014	WNK1
regulation of dendritic spine development	1	210.7×	0.014	KIF1A

Therapeutics

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 3 · Undrugged: 6

Druggability breadth: 5 of 9 evidence-associated genes (56%) 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
SCN1A	MEXILETINE HYDROCHLORIDE
SCN2A	BEPRIDIL
SCN9A	IMIPRAMINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN2A	99	4
SCN1A	94	4
SCN9A	36	4
WNK1	0	0
TTC21B	0	0
RETREG1	0	0
CSRNP3	0	0
SCN1A-AS1	0	0
KIF1A	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MEXILETINE HYDROCHLORIDE	4	SCN1A, SCN9A
BEPRIDIL	4	SCN1A, SCN2A
DIBUCAINE	4	SCN1A, SCN2A
ARTICAINE	4	SCN1A, SCN2A
BUPIVACAINE	4	SCN1A, SCN2A
IMIPRAMINE	4	SCN1A, SCN2A, SCN9A
DROPERIDOL	4	SCN1A, SCN2A
DICYCLOMINE	4	SCN1A, SCN2A
TETRABENAZINE	4	SCN1A, SCN2A
PHENIRAMINE	4	SCN1A, SCN2A
PRILOCAINE	4	SCN1A, SCN2A
PROPOXYCAINE	4	SCN1A, SCN2A
PROPARACAINE	4	SCN1A, SCN2A
HEXYLCAINE	4	SCN1A, SCN2A
PRAMOXINE	4	SCN1A, SCN2A
BENOXINATE	4	SCN1A, SCN2A
QUINIDINE	4	SCN1A, SCN2A
FELODIPINE	4	SCN1A, SCN2A
PHENYTOIN	4	SCN1A, SCN2A
QUININE	4	SCN1A, SCN2A
NISOLDIPINE	4	SCN1A, SCN2A
NIFEDIPINE	4	SCN1A, SCN2A, SCN9A
PRAZOSIN	4	SCN1A, SCN2A
DILTIAZEM	4	SCN1A, SCN2A, SCN9A
PRENYLAMINE	4	SCN1A, SCN2A
COCAINE	4	SCN1A, SCN2A
TRIFLUOPERAZINE	4	SCN1A, SCN2A
CINNARIZINE	4	SCN1A, SCN2A
THIORIDAZINE	4	SCN1A, SCN2A
ETIDOCAINE	4	SCN1A, SCN2A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
SCN9A	428	Binding:395, Functional:29, ADMET:3, Toxicity:1
SCN2A	203	Binding:172, Functional:20, ADMET:10, Toxicity:1
WNK1	165	Binding:165
SCN1A	149	Binding:115, Functional:18, ADMET:14, Toxicity:2
KIF1A	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
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
WNK1	165
SCN1A	149
SCN2A	203
SCN9A	428

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; 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)
MEXILETINE HYDROCHLORIDE	4	SCN1A, SCN9A
BEPRIDIL	4	SCN1A, SCN2A
DIBUCAINE	4	SCN1A, SCN2A
ARTICAINE	4	SCN1A, SCN2A
BUPIVACAINE	4	SCN1A, SCN2A
IMIPRAMINE	4	SCN1A, SCN2A, SCN9A
DROPERIDOL	4	SCN1A, SCN2A
DICYCLOMINE	4	SCN1A, SCN2A
TETRABENAZINE	4	SCN1A, SCN2A
PHENIRAMINE	4	SCN1A, SCN2A
PRILOCAINE	4	SCN1A, SCN2A
PROPOXYCAINE	4	SCN1A, SCN2A
PROPARACAINE	4	SCN1A, SCN2A
HEXYLCAINE	4	SCN1A, SCN2A
PRAMOXINE	4	SCN1A, SCN2A
BENOXINATE	4	SCN1A, SCN2A
QUINIDINE	4	SCN1A, SCN2A
FELODIPINE	4	SCN1A, SCN2A
PHENYTOIN	4	SCN1A, SCN2A
QUININE	4	SCN1A, SCN2A
NISOLDIPINE	4	SCN1A, SCN2A
NIFEDIPINE	4	SCN1A, SCN2A, SCN9A
PRAZOSIN	4	SCN1A, SCN2A
DILTIAZEM	4	SCN1A, SCN2A, SCN9A
PRENYLAMINE	4	SCN1A, SCN2A
COCAINE	4	SCN1A, SCN2A
TRIFLUOPERAZINE	4	SCN1A, SCN2A
CINNARIZINE	4	SCN1A, SCN2A
THIORIDAZINE	4	SCN1A, SCN2A
ETIDOCAINE	4	SCN1A, SCN2A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	SCN1A, SCN2A, SCN9A
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	WNK1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	TTC21B, RETREG1, CSRNP3, SCN1A-AS1, KIF1A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
WNK1	165	—
TTC21B	0	—
RETREG1	0	—
CSRNP3	0	—
SCN1A-AS1	0	—
KIF1A	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.