Progressive myoclonus epilepsy

Summary

Progressive myoclonus epilepsy (MONDO:0020074) is a disease (an umbrella term covering 15 Mondo subtypes) caused by variants in KCNC1, NUS1, and SCARB2, with 18 cohort genes and 2 clinical trials.

At a glance

• Causal genes: KCNC1 (GenCC Definitive), NUS1 (GenCC Strong), SCARB2 (GenCC Strong)
• Umbrella term: 15 Mondo subtypes
• Cohort genes: 18
• ClinVar variants: 1,280
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	progressive myoclonus epilepsy
Mondo ID	MONDO:0020074
MeSH	D020191
OMIM	254800
Orphanet	98261
DOID	DOID:891
ICD-11	173613583
NCIT	C7636
SNOMED CT	267581004
UMLS	C0751778
MedGen	199732
GARD	0007140
NORD	1617
Is cancer (heuristic)	no

Also known as: epilepsy, progressive myoclonic · familial progressive myoclonic epilepsy · PME · progressive myoclonic epilepsy · progressive myoclonic epilepsy (disorder) [ambiguous] · progressive myoclonus epilepsy

Data availability: 1,280 ClinVar variants · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 15 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neurological disease › progressive myoclonus epilepsy

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, paroxysmal extreme pain 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, 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

Subtypes (15): Lafora disease, Unverricht-Lundborg syndrome, action myoclonus-renal failure syndrome, MERRF syndrome, familial encephalopathy with neuroserpin inclusion bodies, neuronal ceroid lipofuscinosis 8 northern epilepsy variant, progressive myoclonic epilepsy type 3, epilepsy, progressive myoclonic, 1B, progressive myoclonic epilepsy type 6, progressive myoclonic epilepsy type 7, progressive myoclonic epilepsy type 8, progressive myoclonic epilepsy type 9, early-onset Lafora body disease, epilepsy, progressive myoclonic, 11, epilepsy, progressive myoclonic, 12

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:

290 uncertain significance, 205 likely benign, 31 conflicting classifications of pathogenicity, 26 pathogenic, 20 benign/likely benign, 15 benign, 9 pathogenic/likely pathogenic, 4 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1456083	NC_000004.11:g.(?76481293)(77700330_?)del	ART3	Pathogenic	criteria provided, single submitter
1074795	NC_000021.8:g.(?45194083)(45196150_?)del	CSTB	Pathogenic	criteria provided, single submitter
1455136	NM_000100.4(CSTB):c.121del (p.Val41fs)	CSTB	Pathogenic	criteria provided, single submitter
161418	NM_000100.4(CSTB):c.136C>T (p.Gln46Ter)	CSTB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1807163	NM_000100.4(CSTB):c.145del (p.Ala49fs)	CSTB	Pathogenic	criteria provided, multiple submitters, no conflicts
1047431	NM_005670.4(EPM2A):c.794A>G (p.His265Arg)	EPM2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068477	NM_005670.4(EPM2A):c.302-2A>G	EPM2A	Pathogenic	criteria provided, multiple submitters, no conflicts
1075527	NM_005670.4(EPM2A):c.108_139del (p.Ala37fs)	EPM2A	Pathogenic	criteria provided, multiple submitters, no conflicts
1393093	NM_005670.4(EPM2A):c.302-1G>C	EPM2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1418032	NM_005670.4(EPM2A):c.759_760insATGCA (p.Ala254fs)	EPM2A	Pathogenic	criteria provided, single submitter
1451802	NM_005670.4(EPM2A):c.258C>G (p.Tyr86Ter)	EPM2A	Pathogenic	criteria provided, multiple submitters, no conflicts
1454028	NM_005670.4(EPM2A):c.934dup (p.Arg312fs)	EPM2A	Pathogenic	criteria provided, single submitter
1456100	NC_000006.11:g.(?146056334)(146056634_?)del	EPM2A	Pathogenic	criteria provided, single submitter
1459452	NC_000006.11:g.(?145948552)(145956642_?)del	EPM2A	Pathogenic	criteria provided, single submitter
1471835	NM_005670.4(EPM2A):c.92_124del (p.Arg31_Arg41del)	EPM2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1510680	NM_005670.4(EPM2A):c.301+1G>T	EPM2A	Pathogenic	criteria provided, multiple submitters, no conflicts
2020620	NM_005670.4(EPM2A):c.301+2T>C	EPM2A	Pathogenic	criteria provided, single submitter
2024510	NM_005670.4(EPM2A):c.96G>A (p.Trp32Ter)	EPM2A	Pathogenic	criteria provided, single submitter
2136482	NM_005670.4(EPM2A):c.256T>G (p.Tyr86Asp)	EPM2A	Pathogenic	criteria provided, single submitter
1073493	NM_004287.5(GOSR2):c.89_90del (p.Val30fs)	GOSR2	Pathogenic	criteria provided, single submitter
1372090	NM_004287.5(GOSR2):c.301C>T (p.Arg101Ter)	GOSR2	Pathogenic	criteria provided, single submitter
1410870	NM_004287.5(GOSR2):c.16C>T (p.Gln6Ter)	GOSR2	Pathogenic	criteria provided, single submitter
1451722	NM_004287.5(GOSR2):c.161del (p.Leu54fs)	GOSR2	Pathogenic	criteria provided, single submitter
1458379	NC_000017.10:g.(?44845686)(45016126_?)del	GOSR2	Pathogenic	criteria provided, single submitter
211092	NM_004287.5(GOSR2):c.336+1G>A	GOSR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2123629	NM_004287.5(GOSR2):c.262C>T (p.Gln88Ter)	GOSR2	Pathogenic	criteria provided, single submitter
162519	NM_001112741.2(KCNC1):c.959G>A (p.Arg320His)	KCNC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1403169	NM_004287.5(GOSR2):c.210del (p.Asp71fs)	LOC126862578	Pathogenic	criteria provided, single submitter
1441270	NM_005506.4(SCARB2):c.850del (p.Tyr284fs)	SCARB2	Pathogenic	criteria provided, single submitter
1451782	NM_005506.4(SCARB2):c.235del (p.Glu79fs)	SCARB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 25 · Orphanet: 19 · 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
KCNC1	Definitive	Autosomal dominant	progressive myoclonic epilepsy type 7	8
SCARB2	Definitive	Autosomal recessive	action myoclonus-renal failure syndrome	5
NUS1	Strong	Autosomal dominant	progressive myoclonus epilepsy	8
C9orf72	Limited	Autosomal dominant	progressive myoclonus epilepsy	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCARB2	Orphanet:163696	Action myoclonus-renal failure syndrome
SCARB2	Orphanet:308	Progressive myoclonic epilepsy type 1
SCARB2	Orphanet:77259	Gaucher disease type 1
KCNC1	Orphanet:435438	Progressive myoclonic epilepsy type 7
NUS1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
C9orf72	Orphanet:100069	Semantic dementia
C9orf72	Orphanet:100070	Progressive non-fluent aphasia
C9orf72	Orphanet:275864	Behavioral variant of frontotemporal dementia
C9orf72	Orphanet:275872	Frontotemporal dementia with motor neuron disease
C9orf72	Orphanet:401901	Huntington disease-like syndrome due to C9ORF72 expansions
C9orf72	Orphanet:803	Amyotrophic lateral sclerosis
PRICKLE2	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
PRICKLE2	Orphanet:402082	Progressive myoclonic epilepsy type 5
KCTD7	Orphanet:263516	Progressive myoclonic epilepsy type 3
KCTD7	Orphanet:699708	CLN14 disease
CSTB	Orphanet:248	Autosomal recessive hypohidrotic ectodermal dysplasia
CSTB	Orphanet:308	Progressive myoclonic epilepsy type 1
EPM2A	Orphanet:501	Lafora disease
GOSR2	Orphanet:280620	Progressive myoclonic epilepsy type 6

Cohort genes → proteins

18 cohort genes, 16 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	18

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCARB2	HGNC:1665	ENSG00000138760	Q14108	Lysosome membrane protein 2	gencc,clinvar
KCNC1	HGNC:6233	ENSG00000129159	P48547	Voltage-gated potassium channel KCNC1	gencc,clinvar
NUS1	HGNC:21042	ENSG00000153989	Q96E22	Dehydrodolichyl diphosphate synthase complex subunit NUS1	gencc
C9orf72	HGNC:28337	ENSG00000147894	Q96LT7	Guanine nucleotide exchange factor C9orf72	gencc
PRICKLE2	HGNC:20340	ENSG00000163637	Q7Z3G6	Prickle-like protein 2	clinvar
KCTD7	HGNC:21957	ENSG00000243335	Q96MP8	BTB/POZ domain-containing protein KCTD7	clinvar
RRP1B	HGNC:23818	ENSG00000160208	Q14684	Ribosomal RNA processing protein 1 homolog B	clinvar
CSTB	HGNC:2482	ENSG00000160213	P04080	Cystatin-B	clinvar
LRRC37A2	HGNC:32404	ENSG00000238083	A6NM11	Leucine-rich repeat-containing protein 37A2	clinvar
AGPAT3	HGNC:326	ENSG00000160216	Q9NRZ7	1-acyl-sn-glycerol-3-phosphate acyltransferase gamma	clinvar
EPM2A	HGNC:3413	ENSG00000112425	B3EWF7	Laforin, isoform 9	clinvar
PRICKLE2-AS1	HGNC:40916	ENSG00000241572		PRICKLE2 antisense RNA 1	clinvar
GOSR2	HGNC:4431	ENSG00000108433	O14653	Golgi SNAP receptor complex member 2	clinvar
EPM2A-DT	HGNC:48990	ENSG00000235652		EPM2A divergent transcript	clinvar
HSF2BP	HGNC:5226	ENSG00000160207	O75031	Heat shock factor 2-binding protein	clinvar
ART3	HGNC:725	ENSG00000156219	Q13508	Ecto-ADP-ribosyltransferase 3	clinvar
ABCG1	HGNC:73	ENSG00000160179	P45844	ATP-binding cassette sub-family G member 1	clinvar
PDXK	HGNC:8819	ENSG00000160209	O00764	Pyridoxal kinase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCARB2	Lysosome membrane protein 2	Acts as a lysosomal receptor for glucosylceramidase (GBA1) targeting.
KCNC1	Voltage-gated potassium channel KCNC1	Voltage-gated potassium channel that opens in response to the voltage difference across the membrane and through which potassium ions pass in accordance with their electrochemical gradient.
NUS1	Dehydrodolichyl diphosphate synthase complex subunit NUS1	With DHDDS, forms the dehydrodolichyl diphosphate synthase (DDS) complex, an essential component of the dolichol monophosphate (Dol-P) biosynthetic machinery.
C9orf72	Guanine nucleotide exchange factor C9orf72	Acts as a guanine-nucleotide releasing factor (GEF) for Rab GTPases by promoting the conversion of inactive RAB-GDP to the active form RAB-GTP.
PRICKLE2	Prickle-like protein 2	Is involved in the organization and maintenance of axon initial segment (AIS) architecture, likely cooperating with IGSF9B to regulate ANK3/ANKG localization to AIS.
KCTD7	BTB/POZ domain-containing protein KCTD7	May be involved in the control of excitability of cortical neurons.
RRP1B	Ribosomal RNA processing protein 1 homolog B	Positively regulates DNA damage-induced apoptosis by acting as a transcriptional coactivator of proapoptotic target genes of the transcriptional activator E2F1.
CSTB	Cystatin-B	This is an intracellular thiol proteinase inhibitor.
AGPAT3	1-acyl-sn-glycerol-3-phosphate acyltransferase gamma	Converts 1-acyl-sn-glycerol-3-phosphate (lysophosphatidic acid or LPA) into 1,2-diacyl-sn-glycerol-3-phosphate (phosphatidic acid or PA) by incorporating an acyl moiety at the sn-2 position of the glycerol backbone.
GOSR2	Golgi SNAP receptor complex member 2	Involved in transport of proteins from the cis/medial-Golgi to the trans-Golgi network.
HSF2BP	Heat shock factor 2-binding protein	Meiotic recombination factor component of recombination bridges involved in meiotic double-strand break repair.
ABCG1	ATP-binding cassette sub-family G member 1	Catalyzes the efflux of phospholipids such as sphingomyelin, cholesterol and its oxygenated derivatives like 7beta-hydroxycholesterol and this transport is coupled to hydrolysis of ATP.
PDXK	Pyridoxal kinase	Catalyzes the phosphorylation of the dietary vitamin B6 vitamers pyridoxal (PL), pyridoxine (PN) and pyridoxamine (PM) to form pyridoxal 5’-phosphate (PLP), pyridoxine 5’-phosphate (PNP) and pyridoxamine 5’-phosphate (PMP), respectively.

Protein-family classification

Druggable: 6 · Difficult: 1 · Unknown: 11 · 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	1	6.2×	0.485
Phosphatase	1	4.7×	0.485
Transporter	1	4.3×	0.485
Kinase	1	1.5×	0.565
Enzyme (other)	2	1.3×	0.565
Other/Unknown	11	1.1×	0.565
Transcription factor	1	0.5×	0.902

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCARB2	Other/Unknown	no		CD36_fam, LimpII
KCNC1	Ion channel	yes		BTB/POZ_dom, T1-type_BTB, K_chnl_volt-dep_Kv
NUS1	Enzyme (other)	yes	2.5.1.87	UPP_synth-like, UPP_synth-like_sf, Nus1/NgBR
C9orf72	Other/Unknown	no		C9orf72
PRICKLE2	Transcription factor	no		Znf_LIM, PET_domain, PET_prickle
KCTD7	Other/Unknown	no		BTB/POZ_dom, T1-type_BTB, SKP1/BTB/POZ_sf
RRP1B	Other/Unknown	no		RRP1
CSTB	Other/Unknown	no		Cystatin_dom, Prot_inh_stefin, Prot_inh_cystat_CS
LRRC37A2	Other/Unknown	no		Leu-rich_rpt, Leu-rich_rpt_typical-subtyp, LRRC37
AGPAT3	Enzyme (other)	yes	2.3.1.51	Plipid/glycerol_acylTrfase, Acyltransf_C
EPM2A	Phosphatase	yes	3.1.3.16	Dual-sp_phosphatase_cat-dom, Tyr_Pase_dom, CBM20
PRICKLE2-AS1	Other/Unknown	no
GOSR2	Other/Unknown	no		SNARE, GOSR2/Membrin/Bos1, v-SNARE_N_sf
EPM2A-DT	Other/Unknown	no
HSF2BP	Other/Unknown	no		ARM-like, ARM-type_fold, HSF2BP
ART3	Other/Unknown	no		ART, ADP-ribosyltransferase_ARG
ABCG1	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, Pigment_permease/Abcg
PDXK	Kinase	yes	2.7.1.35	PyrdxlKinase, PM/HMP-P_kinase-1, Ribokinase-like

Expression context

Cohort genes with no expression data: 0.

14 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)	18
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right testis	3
hindlimb stylopod muscle	3
left testis	3
germinal epithelium of ovary	2
cerebellar hemisphere	2
colonic epithelium	2
ganglionic eminence	2
biceps brachii	2
male germ line stem cell (sensu Vertebrata) in testis	2
inferior vagus X ganglion	1
subthalamic nucleus	1
cerebellar cortex	1
right hemisphere of cerebellum	1
endometrium	1
islet of Langerhans	1
tibia	1
leukocyte	1
monocyte	1
mucosa of paranasal sinus	1
cauda epididymis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCARB2	298	ubiquitous	marker	inferior vagus X ganglion, subthalamic nucleus, germinal epithelium of ovary
KCNC1	186	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
NUS1	255	broad	marker	endometrium, tibia, islet of Langerhans
C9orf72	250	ubiquitous	marker	monocyte, leukocyte, mucosa of paranasal sinus
PRICKLE2	233	ubiquitous	marker	oviduct epithelium, cauda epididymis, colonic epithelium
KCTD7	261	ubiquitous	yes	cortical plate, ganglionic eminence, C1 segment of cervical spinal cord
RRP1B	286	ubiquitous	marker	germinal epithelium of ovary, gingival epithelium, gingiva
CSTB	300	ubiquitous	marker	lower esophagus mucosa, tongue squamous epithelium, pharyngeal mucosa
LRRC37A2	134		yes	right uterine tube, right testis, cerebellar hemisphere
AGPAT3	274	ubiquitous	marker	lateral globus pallidus, middle temporal gyrus, Brodmann (1909) area 23
EPM2A	281	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, biceps brachii, hindlimb stylopod muscle
PRICKLE2-AS1	86		yes	male germ line stem cell (sensu Vertebrata) in testis, hindlimb stylopod muscle, ganglionic eminence
GOSR2	289	ubiquitous	marker	buccal mucosa cell, left testis, right testis
EPM2A-DT	217	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, colonic epithelium, calcaneal tendon
HSF2BP	124	ubiquitous	yes	primordial germ cell in gonad, left testis, testis
ART3	199	broad	marker	gastrocnemius, hindlimb stylopod muscle, biceps brachii
ABCG1	270	ubiquitous	marker	right adrenal gland, left adrenal gland, right adrenal gland cortex
PDXK	295	ubiquitous	marker	left testis, right testis, adult organism

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SCARB2	5,405
RRP1B	3,651
C9orf72	3,126
KCNC1	3,000
GOSR2	2,196
ABCG1	2,178
AGPAT3	2,081
NUS1	2,058
CSTB	1,987
PDXK	1,899

Intra-cohort edges

A	B	Sources
ABCG1	SCARB2	string_interaction
CSTB	KCTD7	string_interaction
CSTB	RRP1B	string_interaction
HSF2BP	RRP1B	string_interaction
PDXK	RRP1B	string_interaction

Structural data

PDB: 11 · AlphaFold-only: 5 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCARB2	Q14108	10
KCNC1	P48547	10
PDXK	O00764	10
NUS1	Q96E22	9
ABCG1	P45844	5
C9orf72	Q96LT7	4
HSF2BP	O75031	4
CSTB	P04080	3
RRP1B	Q14684	2
EPM2A	B3EWF7	2
GOSR2	O14653	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AGPAT3	Q9NRZ7	94.63
KCTD7	Q96MP8	81.67
ART3	Q13508	74.56
PRICKLE2	Q7Z3G6	56.41
LRRC37A2	A6NM11	42.32

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 38. Enrichment computed across 18 evidence-associated genes (11 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 11 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective DHDDS causes RP59	1	519.1×	0.055	NUS1
Vitamin B6 activation to pyridoxal phosphate	1	346.1×	0.055	PDXK
Synthesis of dolichyl-phosphate	1	148.3×	0.073	NUS1
Myoclonic epilepsy of Lafora	1	115.3×	0.073	EPM2A
HDL remodeling	1	103.8×	0.073	ABCG1
Glycogen synthesis	1	74.2×	0.085	EPM2A
ABC transporters in lipid homeostasis	1	54.6×	0.099	ABCG1
Plasma lipoprotein remodeling	1	43.3×	0.109	ABCG1
NR1H2 and NR1H3-mediated signaling	1	35.8×	0.116	ABCG1
Cargo concentration in the ER	1	30.5×	0.116	GOSR2
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	1	28.1×	0.116	ABCG1
Synthesis of PA	1	26.6×	0.116	AGPAT3
Intra-Golgi traffic	1	23.6×	0.116	GOSR2
Voltage gated Potassium channels	1	22.1×	0.116	KCNC1
Plasma lipoprotein assembly, remodeling, and clearance	1	20.8×	0.116	ABCG1
XBP1(S) activates chaperone genes	1	19.6×	0.116	GOSR2
COPI-independent Golgi-to-ER retrograde traffic	1	18.9×	0.116	AGPAT3
Post-translational modification: synthesis of GPI-anchored proteins	1	15.3×	0.131	ART3
COPII-mediated vesicle transport	1	14.8×	0.131	GOSR2
Potassium Channels	1	12.2×	0.144	KCNC1
Neutrophil degranulation	2	4.2×	0.144	CSTB, PDXK
ABC-family protein mediated transport	1	11.0×	0.150	ABCG1
COPI-mediated anterograde transport	1	10.0×	0.156	GOSR2
Cargo recognition for clathrin-mediated endocytosis	1	9.5×	0.156	SCARB2
Signaling by Nuclear Receptors	1	9.3×	0.156	ABCG1
Post-translational protein modification	2	3.5×	0.160	KCTD7, ART3
Clathrin-mediated endocytosis	1	7.8×	0.171	SCARB2
Class I MHC mediated antigen processing & presentation	1	6.4×	0.199	KCTD7
Neddylation	1	4.3×	0.273	KCTD7
Neuronal System	1	4.0×	0.273	KCNC1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 14 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
pyridoxal 5’-phosphate salvage	1	1203.7×	0.022	PDXK
pyridoxal metabolic process	1	1203.7×	0.022	PDXK
regulation of carbohydrate catabolic process	1	1203.7×	0.022	SCARB2
regulation of glucosylceramide catabolic process	1	1203.7×	0.022	SCARB2
positive regulation of macroautophagy	2	75.2×	0.022	C9orf72, EPM2A
dolichyl diphosphate biosynthetic process	1	601.9×	0.026	NUS1
pyridoxamine metabolic process	1	601.9×	0.026	PDXK
regulation of endosome organization	1	601.9×	0.026	SCARB2
negative regulation of phosphatase activity	1	401.2×	0.026	EPM2A
glycoprotein transport	1	401.2×	0.026	ABCG1
cellular response to high density lipoprotein particle stimulus	1	401.2×	0.026	ABCG1
response to nerve growth factor	1	401.2×	0.026	KCNC1
aminophospholipid transport	1	300.9×	0.026	SCARB2
regulation of intracellular cholesterol transport	1	300.9×	0.026	NUS1
negative regulation of dephosphorylation	1	300.9×	0.026	EPM2A
habituation	1	300.9×	0.026	EPM2A
globus pallidus development	1	240.7×	0.026	KCNC1
regulation of protein import into nucleus	1	240.7×	0.026	EPM2A
protein localization to axon	1	240.7×	0.026	PRICKLE2
endosome to plasma membrane protein transport	1	240.7×	0.026	SCARB2
cholesterol homeostasis	2	22.3×	0.026	NUS1, ABCG1
intracellular glutamate homeostasis	1	200.6×	0.027	KCTD7
regulation of lysosome organization	1	200.6×	0.027	SCARB2
response to lipid	1	172.0×	0.027	ABCG1
negative regulation of exocytosis	1	172.0×	0.027	C9orf72
regulation of actin filament organization	1	172.0×	0.027	C9orf72
response to light intensity	1	150.5×	0.027	KCNC1
response to potassium ion	1	150.5×	0.027	KCNC1
carbohydrate phosphorylation	1	150.5×	0.027	EPM2A
response to fibroblast growth factor	1	150.5×	0.027	KCNC1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 17

Druggability breadth: 5 of 18 evidence-associated genes (28%) 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
PDXK	SUNITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PDXK	6	4
SCARB2	0	0
KCNC1	0	0
NUS1	0	0
C9orf72	0	0
PRICKLE2	0	0
KCTD7	0	0
RRP1B	0	0
CSTB	0	0
LRRC37A2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SUNITINIB	4	PDXK
VOLASERTIB	3	PDXK
LUCITANIB	2	PDXK
TG100-115	2	PDXK
FGFR INHIBITOR DEBIO 1347	2	PDXK
BI-2536	2	PDXK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
KCNC1	28	Binding:25, Functional:2, Toxicity:1
PDXK	21	Binding:20, ADMET:1
RRP1B	1	Binding:1
CSTB	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NUS1	2.5.1.87	ditrans,polycis-polyprenyl diphosphate synthase [(2E,6E)-farnesyl diphosphate specific]
AGPAT3	2.3.1.51	1-acylglycerol-3-phosphate O-acyltransferase
EPM2A	3.1.3.16	protein-serine/threonine phosphatase
PDXK	2.7.1.35	pyridoxal kinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 16; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

6 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)
SUNITINIB	4	PDXK
VOLASERTIB	3	PDXK
LUCITANIB	2	PDXK
TG100-115	2	PDXK
FGFR INHIBITOR DEBIO 1347	2	PDXK
BI-2536	2	PDXK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PDXK
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	4	KCNC1, NUS1, EPM2A, ABCG1
D	Druggable family + AlphaFold only, no drug	1	AGPAT3
E	Difficult family or no structure, no drug	12	SCARB2, C9orf72, PRICKLE2, KCTD7, RRP1B, CSTB, LRRC37A2, PRICKLE2-AS1, GOSR2, EPM2A-DT (+2 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RRP1B	1	PDXK
SCARB2	0	—
KCNC1	28	—
NUS1	0	—
C9orf72	0	—
PRICKLE2	0	—
KCTD7	0	—
CSTB	1	—
LRRC37A2	0	—
AGPAT3	0	—
EPM2A	0	—
PRICKLE2-AS1	0	—
GOSR2	0	—
EPM2A-DT	0	—
HSF2BP	0	—
ART3	0	—
ABCG1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06593951	Not specified	RECRUITING	Registry and Natural History Study for Progressive Myoclonus Epilepsy Type 1 (EPM1)
NCT06923241	Not specified	COMPLETED	Nutri-score Labelling in a UK Restaurant Setting: a Randomised Control Trial