Paroxysmal extreme pain disorder

Summary

Paroxysmal extreme pain disorder (MONDO:0008179) is a disease caused by SCN9A (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SCN9A (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 257
• Phenotypes (HPO): 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

2 HPO clinical features (Orphanet curated; top 2 by frequency):

HPO ID	Term	Frequency
HP:0001250	Seizure	Very frequent (80-99%)
HP:0002019	Constipation	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	paroxysmal extreme pain disorder
Mondo ID	MONDO:0008179
MeSH	C563475
OMIM	167400
Orphanet	46348
DOID	DOID:0111537
ICD-11	9604457
NCIT	C125385
SNOMED CT	699190008
UMLS	C1833661
MedGen	331565
GARD	0012854
Is cancer (heuristic)	no

Also known as: familial rectal pain · familial rectal syndrome · paroxysmal extreme pain disorder · PEPD · submandibular, ocular, and rectal pain with flushing

Data availability: 257 ClinVar variants · 2 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neurological disease › paroxysmal extreme pain disorder

Related subtypes (263): leukoencephalopathy, megalencephalic, epilepsy, familial adult myoclonic, encephalopathy, acute, infection-induced, GLUT1 deficiency syndrome, paraganglioma, familial hemiplegic migraine, stutter disorder, specific language impairment, anencephaly, complex cortical dysplasia with other brain malformations, familial periodic paralysis, tuberous sclerosis, essential tremor, intracranial extraskeletal myxoid chondrosarcoma, Parkinson disease, progressive external ophthalmoplegia, myalgic encephalomeyelitis/chronic fatigue syndrome, cerebral amyloid angiopathy, congenital nystagmus, Angelman syndrome, nevoid basal cell carcinoma syndrome, Chiari malformation type I, choreoathetosis, familial inverted, cluster headache, familial, coloboma of optic nerve, craniosynostosis-Dandy-Walker malformation-hydrocephalus syndrome, major affective disorder 1, neurohypophyseal diabetes insipidus, Duane retraction syndrome, lateral meningocele syndrome, encephalopathy, recurrent, of childhood, familial congenital palsy of trochlear nerve, Gerstmann-Straussler-Scheinker syndrome, Tourette syndrome, Guillain-Barre syndrome, familial, Frey syndrome, melanoma and neural system tumor syndrome, narcolepsy 1, linear nevus sebaceous syndrome, oculocerebrocutaneous syndrome, obsessive-compulsive disorder, familial pterygium of the conjunctiva, retinal detachment, Sturge-Weber syndrome, DiGeorge syndrome, blue color blindness, velocardiofacial syndrome, von Hippel-Lindau disease, arthrogryposis, Chiari malformation type II, Behr syndrome, isolated cerebellar hypoplasia/agenesis, bilateral striopallidodentate calcinosis, Griscelli syndrome type 1, multiple pterygium-malignant hyperthermia syndrome, corpus callosum, agenesis of, Riley-Day syndrome, glutaryl-CoA dehydrogenase deficiency, normal pressure hydrocephalus, hyperlexia, Johanson-Blizzard syndrome, macrocephaly/megalencephaly syndrome, autosomal recessive, neurocutaneous melanocytosis, myosclerosis, Bailey-Bloch congenital myopathy, choroid plexus papilloma, pyridoxine-dependent epilepsy, NPHP3-related Meckel-like syndrome, familial hemophagocytic lymphohistiocytosis type 1, mismatch repair cancer syndrome 1, orofaciodigital syndrome type 6, X-linked immunoneurologic disorder, HSD10 mitochondrial disease, rolandic epilepsy, intellectual disability, and speech dyspraxia, X-linked, severe neonatal-onset encephalopathy with microcephaly, dilated cardiomyopathy 3B, red-green color blindness, red color blindness, iris hypoplasia with glaucoma, major affective disorder 2, band heterotopia of brain, Brody myopathy, chorea, remitting, with nystagmus and cataract, isolated hereditary congenital facial paralysis, childhood apraxia of speech, megalencephaly-capillary malformation-polymicrogyria syndrome, familial infantile myoclonic epilepsy, TH-deficient dopa-responsive dystonia, glycine encephalopathy, spongiform encephalopathy with neuropsychiatric features, bilateral frontoparietal polymicrogyria, B4GALT1-congenital disorder of glycosylation, angioid streaks, familial meningioma, biotin-responsive basal ganglia disease, anxiety, rolandic epilepsy-paroxysmal exercise-induced dystonia-writer’s cramp syndrome, specific phobia, bradyopsia, endogenous depression, narcolepsy 3, permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome, myofibrillar myopathy 5, major affective disorder 3, achromatopsia 6, pyridoxal phosphate-responsive seizures, prosopagnosia, hereditary, brain-lung-thyroid syndrome, polyhydramnios, megalencephaly, and symptomatic epilepsy, major affective disorder 4, major affective disorder 5, major affective disorder 6, major affective disorder 8, major affective disorder 7, major affective disorder 9, age-related hearing impairment 1, bilateral parasagittal parieto-occipital polymicrogyria, age-related hearing impairment 2, combined pituitary hormone deficiencies, genetic form, cirrhosis - dystonia - polycythemia - hypermanganesemia syndrome, rhabdoid tumor predisposition syndrome 2, infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly, schizophrenia 15, schizophrenia 16, occipital pachygyria and polymicrogyria, familial retinal arterial macroaneurysm, narcolepsy 7, bilateral generalized polymicrogyria, myoclonus, familial, familial hyperprolactinemia, proximal myopathy with extrapyramidal signs, sacral agenesis-abnormal ossification of the vertebral bodies-persistent notochordal canal syndrome, polymicrogyria, bilateral perisylvian, autosomal recessive, ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome, cerebellar-facial-dental syndrome, myopathy due to calsequestrin and SERCA1 protein overload, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, progressive essential tremor-speech impairment-facial dysmorphism-intellectual disability-abnormal behavior syndrome, Brown syndrome, epilepsy with myoclonic atonic seizures, polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, SLC39A8-CDG, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, TELO2-related intellectual disability-neurodevelopmental disorder, hypermanganesemia with dystonia 2, aniridia 2, aniridia 3, severe congenital nemaline myopathy, typical nemaline myopathy, childhood-onset nemaline myopathy, adult-onset nemaline myopathy, myopic macular degeneration, 2-hydroxyglutaric aciduria, benign neonatal seizures, qualitative or quantitative defects of alpha-sarcoglycan, qualitative or quantitative defects of beta-sarcoglycan, qualitative or quantitative defects of gamma-sarcoglycan, qualitative or quantitative defects of delta-sarcoglycan, neuromuscular disease caused by qualitative or quantitative defects of dysferlin, caveolinopathy, neuromuscular disease caused by qualitative or quantitative defects of perlecan, neuromuscular disease caused by qualitative or quantitative defects of TRIM32, qualitative or quantitative defects of protein involved in O-glycosylation of alpha-dystroglycan, qualitative or quantitative defects of desmin, neuromuscular disease caused by qualitative or quantitative defects of telethonin, neuromuscular disease caused by qualitative or quantitative defects of beta-myosin heavy chain (MYH7), neuromuscular disease caused by qualitative or quantitative defects of plectin, spastic quadriplegic cerebral palsy, congenital stationary night blindness, holoprosencephaly, congenital hydrocephalus, intracranial berry aneurysm, familial congenital mirror movements, Moebius syndrome-axonal neuropathy-hypogonadotropic hypogonadism syndrome, Moyamoya disease, familial Alzheimer-like prion disease, phakomatosis pigmentokeratotica, benign familial infantile epilepsy, inborn aminoacylase deficiency, familial partial epilepsy, familial isolated pituitary adenoma, Hoyeraal-Hreidarsson syndrome, hereditary retinoblastoma, familial syringomyelia, PrP systemic amyloidosis, Prader-Willi-like syndrome, bilirubin encephalopathy, microcephaly-complex motor and sensory axonal neuropathy syndrome, undetermined early-onset epileptic encephalopathy, congenital insensitivity to pain with severe intellectual disability, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, familial schizencephaly, lissencephaly spectrum disorders, Li-Fraumeni syndrome, multiminicore myopathy, parietal foramina, Ritscher-Schinzel syndrome, inherited retinal dystrophy, folinic acid-responsive seizures, megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome, nonsyndromic genetic hearing loss, progressive myoclonus epilepsy, pontocerebellar hypoplasia, cerebral lipidosis with dementia, inherited vitreoretinopathy, periventricular nodular heterotopia, PEHO-like syndrome, familial porencephaly, X-linked deafness, hereditary progressive chorea without dementia, hereditary hyperekplexia, neurofibromatosis, inherited orthostatic hypotension, auditory neuropathy, retinal ciliopathy, Behrens Baumann dust syndrome, inherited reflex epilepsy, inherited neurodegenerative disorder, febrile seizures, familial, 11, famililal cerebral cavernous malformations, familial panic disorder, microangiopathy and leukoencephalopathy, pontine, autosomal dominant, schizophrenia 19, infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndrome, PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, cathepsin a-related arteriopathy-strokes-leukoencephalopathy, parkinsonism with polyneuropathy, central nervous system lupus, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, inherited dystonia, encephalopathy due to mitochondrial and peroxisomal fission defect, alpha-actinopathy, dystonia, dopa-responsive, with or without hyperphenylalaninemia, autosomal recessive, TPM3-related myopathy, Uner Tan Syndrome, TUBB3-related tubulinopathy, TTN-related myopathy, TPM2-related myopathy, fatty acyl-CoA reductase 1 upregulation, hereditary ataxia, brain malformations with or without urinary tract defects, Mendelian neurodevelopmental disorder, SPAST-related motor disorder, hereditary neuromuscular disease, SERAC1-related neurological disorder, PRRT2-associated paroxysmal movement disorder, hereditary generalized epilepsy, VPS11-related neurological disorder, KIF5A-related neurological disorder, ATP1A3-associated neurological disorder, myopathy caused by variation in POMGNT1, SLC6A3-related dopamine transporter deficiency syndrome, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, dyskinesia with orofacial involvement, autosomal dominant, PAX6-related ocular dysgenesis, neuroocular syndrome, epilepsy, X-linked, with or without impaired intellectual development and dysmorphic features, encephalopathy, acute transient, LSM7-related leukodystrophy and cerebellar atrophy, infection-induced acute-onset axonal neuropathy, Valence-Farazi cerebellar ataxia syndrome, DHDDS-related syndrome

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

257 retrieved; paginated sample, class counts are floors:

99 uncertain significance, 67 conflicting classifications of pathogenicity, 44 benign, 30 benign/likely benign, 8 pathogenic, 4 likely benign, 3 likely pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4531783	NM_001365536.1(SCN9A):c.2575A>T (p.Ile859Phe)	SCN1A-AS1	Pathogenic	criteria provided, single submitter
471143	NM_001365536.1(SCN9A):c.5351del (p.Glu1784fs)	SCN1A-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6357	NM_001365536.1(SCN9A):c.3926T>A (p.Val1309Asp)	SCN1A-AS1	Pathogenic	no assertion criteria provided
6359	NM_001365536.1(SCN9A):c.3928G>T (p.Val1310Phe)	SCN1A-AS1	Pathogenic	criteria provided, multiple submitters, no conflicts
245903	NM_001365536.1(SCN9A):c.4928C>A (p.Ala1643Glu)	SCN9A	Pathogenic	criteria provided, multiple submitters, no conflicts
421969	NM_001365536.1(SCN9A):c.2719C>T (p.Arg907Trp)	SCN9A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
446177	NM_001365536.1(SCN9A):c.4417T>G (p.Phe1473Val)	SCN9A	Pathogenic	no assertion criteria provided
6358	NM_001365536.1(SCN9A):c.3925G>T (p.Val1309Phe)	SCN9A	Pathogenic	no assertion criteria provided
6360	NM_001365536.1(SCN9A):c.4415T>C (p.Ile1472Thr)	SCN9A	Pathogenic	criteria provided, multiple submitters, no conflicts
6361	NM_001365536.1(SCN9A):c.4424C>T (p.Thr1475Ile)	SCN9A	Pathogenic	criteria provided, single submitter
1172783	NM_005896.4(IDH1):c.890G>T (p.Cys297Phe)	IDH1	Likely pathogenic	criteria provided, single submitter
430091	NM_001365536.1(SCN9A):c.4868T>C (p.Leu1623Pro)	SCN9A	Likely pathogenic	criteria provided, single submitter
446178	NM_001365536.1(SCN9A):c.4415T>A (p.Ile1472Asn)	SCN9A	Likely pathogenic	criteria provided, single submitter
130260	NM_001365536.1(SCN9A):c.3002A>G (p.Tyr1001Cys)	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
130272	NM_001365536.1(SCN9A):c.4923T>C (p.Leu1641=)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
157597	NM_001365536.1(SCN9A):c.2248A>G (p.Ile750Val)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193648	NM_001365536.1(SCN9A):c.1238T>C (p.Ile413Thr)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193859	NM_001365536.1(SCN9A):c.1555G>A (p.Glu519Lys)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
195488	NM_001365536.1(SCN9A):c.3684T>C (p.Tyr1228=)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
195592	NM_001365536.1(SCN9A):c.3832C>G (p.Leu1278Val)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
195676	NM_001365536.1(SCN9A):c.4073G>A (p.Arg1358Gln)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
195816	NM_001365536.1(SCN9A):c.4314C>T (p.Val1438=)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
234820	NM_001365536.1(SCN9A):c.5711G>A (p.Arg1904His)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
258885	NM_001365536.1(SCN9A):c.3402G>T (p.Leu1134Phe)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291185	NM_001365536.1(SCN9A):c.1464C>T (p.Leu488=)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
30357	NM_001365536.1(SCN9A):c.2192T>A (p.Ile731Lys)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
331914	NM_001365536.1(SCN9A):c.*2228G>T	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
331915	NM_001365536.1(SCN9A):c.*2226T>G	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
331943	NM_001365536.1(SCN9A):c.*785C>T	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 13 · 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
SCN9A	Strong	Autosomal dominant	paroxysmal extreme pain disorder	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
IDH1	Orphanet:163634	Maffucci syndrome
IDH1	Orphanet:251576	Gliosarcoma
IDH1	Orphanet:251579	Giant cell glioblastoma
IDH1	Orphanet:296	Ollier disease
IDH1	Orphanet:86845	Acute myeloid leukaemia with myelodysplasia-related features
IDH1	Orphanet:99646	Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCN9A	HGNC:10597	ENSG00000169432	Q15858	Sodium channel protein type 9 subunit alpha	gencc,clinvar
IDH1	HGNC:5382	ENSG00000138413	O75874	Isocitrate dehydrogenase [NADP] cytoplasmic	clinvar
SCN1A-AS1	HGNC:54069	ENSG00000236107		SCN1A and SCN9A antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
IDH1	Isocitrate dehydrogenase [NADP] cytoplasmic	Catalyzes the NADP(+)-dependent oxidative decarboxylation of isocitrate (D-threo-isocitrate) to 2-ketoglutarate (2-oxoglutarate), which is required by other enzymes such as the phytanoyl-CoA dioxygenase.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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	1	37.2×	0.080
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN9A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
IDH1	Enzyme (other)	yes	1.1.1.42	Isocitrate_DH_NADP, IsoCit/isopropylmalate_DH_CS, IsoPropMal-DH-like_dom
SCN1A-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
sural nerve	2
dorsal root ganglion	1
stromal cell of endometrium	1
adrenal tissue	1
corpus epididymis	1
jejunal mucosa	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
SCN9A	187	ubiquitous	marker	sural nerve, dorsal root ganglion, stromal cell of endometrium
IDH1	294	ubiquitous	marker	corpus epididymis, jejunal mucosa, adrenal tissue
SCN1A-AS1	129	tissue_specific	marker	sural nerve, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IDH1	5,464
SCN9A	1,575
SCN1A-AS1	0

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IDH1	O75874	61
SCN9A	Q15858	43

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Abnormal conversion of 2-oxoglutarate to 2-hydroxyglutarate	1	5710.0×	0.003	IDH1
NADPH regeneration	1	2855.0×	0.003	IDH1
NFE2L2 regulating TCA cycle genes	1	1903.3×	0.003	IDH1
Interaction between L1 and Ankyrins	1	184.2×	0.016	SCN9A
Phase 0 - rapid depolarisation	1	173.0×	0.016	SCN9A
Sensory perception of taste	1	167.9×	0.016	SCN9A
Sensory perception of sweet, bitter, and umami (glutamate) taste	1	139.3×	0.016	SCN9A
Peroxisomal protein import	1	86.5×	0.023	IDH1
L1CAM interactions	1	60.1×	0.029	SCN9A
Cardiac conduction	1	54.4×	0.029	SCN9A
Sensory Perception	1	47.6×	0.030	SCN9A
Muscle contraction	1	38.6×	0.034	SCN9A
Axon guidance	1	22.6×	0.053	SCN9A
Nervous system development	1	21.5×	0.053	SCN9A
Neutrophil degranulation	1	11.5×	0.090	IDH1
Developmental Biology	1	7.2×	0.134	SCN9A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of phospholipid catabolic process	1	8426.0×	0.001	IDH1
action potential propagation	1	8426.0×	0.001	SCN9A
glyoxylate cycle	1	4213.0×	0.001	IDH1
regulation of phospholipid biosynthetic process	1	4213.0×	0.001	IDH1
isocitrate metabolic process	1	1685.2×	0.002	IDH1
NADPH regeneration	1	1685.2×	0.002	IDH1
detection of mechanical stimulus involved in sensory perception	1	1404.3×	0.002	SCN9A
NADP+ metabolic process	1	766.0×	0.004	IDH1
2-oxoglutarate metabolic process	1	468.1×	0.005	IDH1
behavioral response to pain	1	443.5×	0.005	SCN9A
response to steroid hormone	1	421.3×	0.005	IDH1
detection of temperature stimulus involved in sensory perception of pain	1	421.3×	0.005	SCN9A
female gonad development	1	401.2×	0.005	IDH1
cardiac muscle cell action potential involved in contraction	1	351.1×	0.005	SCN9A
tricarboxylic acid cycle	1	255.3×	0.006	IDH1
neuronal action potential	1	240.7×	0.006	SCN9A
sensory perception of pain	1	187.2×	0.008	SCN9A
glutathione metabolic process	1	175.5×	0.008	IDH1
circadian rhythm	1	122.1×	0.010	SCN9A
response to toxic substance	1	105.3×	0.011	SCN9A
post-embryonic development	1	102.8×	0.011	SCN9A
sodium ion transmembrane transport	1	101.5×	0.011	SCN9A
response to oxidative stress	1	65.3×	0.016	IDH1
inflammatory response	1	18.9×	0.052	SCN9A

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
IDH1	ENASIDENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN9A	36	4
IDH1	10	4
SCN1A-AS1	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
ENASIDENIB	4	IDH1
IVOSIDENIB	4	IDH1
VORASIDENIB	4	IDH1
OLUTASIDENIB	4	IDH1
TEDISAMIL	3	SCN9A
NITRENDIPINE	3	SCN9A
AJMALINE	3	SCN9A
RALFINAMIDE	3	SCN9A
VIXOTRIGINE	3	SCN9A
ELECLAZINE	3	SCN9A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
IDH1	488	Binding:475, Functional:12, ADMET:1
SCN9A	428	Binding:395, Functional:29, ADMET:3, Toxicity:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
IDH1	1.1.1.42	isocitrate dehydrogenase (NADP+)

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN9A	428
IDH1	488

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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
ENASIDENIB	4	IDH1
IVOSIDENIB	4	IDH1
VORASIDENIB	4	IDH1
OLUTASIDENIB	4	IDH1
TEDISAMIL	3	SCN9A
NITRENDIPINE	3	SCN9A
AJMALINE	3	SCN9A
RALFINAMIDE	3	SCN9A
VIXOTRIGINE	3	SCN9A
ELECLAZINE	3	SCN9A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	SCN9A, IDH1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SCN1A-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SCN1A-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.