Spastic ataxia

Summary

Spastic ataxia (MONDO:0017845) is a disease (an umbrella term covering 6 Mondo subtypes) with 65 cohort genes and 2 clinical trials. The dominant Reactome pathway is Platelet homeostasis (4 cohort genes).

At a glance

• Umbrella term: 6 Mondo subtypes
• Cohort genes: 65
• ClinVar variants: 101
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	spastic ataxia
Mondo ID	MONDO:0017845
MeSH	C564815
OMIM	108600
Orphanet	316226
DOID	DOID:0050952
UMLS	C1849156
MedGen	376528
GARD	0021401
Is cancer (heuristic)	no

Also known as: SPAX

Data availability: 101 ClinVar variants.

Disease family

An umbrella term covering 6 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › atactic disorder › hereditary ataxia › spastic ataxia

Related subtypes (19): ataxia with fasciculations, muscular atrophy-ataxia-retinitis pigmentosa-diabetes mellitus syndrome, myoclonus-cerebellar ataxia-deafness syndrome, cataract-ataxia-deafness syndrome, ataxia-hypogonadism-choroidal dystrophy syndrome, ichthyosis-hepatosplenomegaly-cerebellar degeneration syndrome, Richards-Rundle syndrome, spinocerebellar ataxia-dysmorphism syndrome, ataxia-tapetoretinal degeneration syndrome, hereditary spastic paraplegia 7, autosomal dominant sensory ataxia 1, EAST syndrome, juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, hereditary episodic ataxia, tremor-ataxia-central hypomyelination syndrome, hereditary cerebellar ataxia, autosomal recessive ataxia due to PEX16 deficiency, autosomal recessive ataxia due to PEX2 deficiency

Subtypes (6): spastic ataxia 2, spasticity-ataxia-gait anomalies syndrome, autosomal dominant spastic ataxia, autosomal recessive spastic ataxia, spastic ataxia 9, autosomal recessive, spastic ataxia 10, autosomal recessive

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

101 retrieved; paginated sample, class counts are floors:

36 conflicting classifications of pathogenicity, 22 likely pathogenic, 20 pathogenic, 11 uncertain significance, 9 pathogenic/likely pathogenic, 2 benign/likely benign, 1 uncertain significance/uncertain risk allele

ClinVar	Variant (HGVS)	Gene	Classification	Review
1184733	NM_032756.4(HPDL):c.[832G>A;91T>C]		Pathogenic	criteria provided, single submitter
1027468	NM_001368809.2(AMPD2):c.808del (p.Arg270fs)	AMPD2	Pathogenic	criteria provided, single submitter
3077	NM_000487.6(ARSA):c.868C>T (p.Arg290Cys)	ARSA	Pathogenic	criteria provided, multiple submitters, no conflicts
1027522	NM_000702.4(ATP1A2):c.2285-2A>C	ATP1A2	Pathogenic	criteria provided, single submitter
189112	NM_000053.4(ATP7B):c.1745_1746del (p.Ile582fs)	ATP7B	Pathogenic	criteria provided, multiple submitters, no conflicts
1027432	NM_031448.6(C19orf12):c.403dup (p.Ala135fs)	C19orf12	Pathogenic	criteria provided, single submitter
56738	NM_025114.4(CEP290):c.384_387del (p.Asp128fs)	CEP290	Pathogenic	criteria provided, multiple submitters, no conflicts
189201	NM_016035.5(COQ4):c.718C>T (p.Arg240Cys)	COQ4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
915899	NM_016035.5(COQ4):c.305G>A (p.Arg102His)	COQ4	Pathogenic	criteria provided, single submitter
1027524	NM_004820.5(CYP7B1):c.806del (p.Asp269fs)	CYP7B1	Pathogenic	criteria provided, single submitter
1027436	NM_018122.5(DARS2):c.233del (p.Asn78fs)	DARS2	Pathogenic	criteria provided, single submitter
55828	NM_005236.3(ERCC4):c.1730dup (p.Tyr577Ter)	ERCC4	Pathogenic	criteria provided, multiple submitters, no conflicts
1027469	NM_181503.3(EXOSC8):c.269C>G (p.Ser90Ter)	EXOSC8	Pathogenic	criteria provided, single submitter
1338863	NM_001458.5(FLNC):c.5385dup (p.Gly1796fs)	FLNC-AS1	Pathogenic	criteria provided, single submitter
915993	NM_000153.4(GALC):c.673G>A (p.Ala225Thr)	GALC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
941	NM_000404.4(GLB1):c.1051C>T (p.Arg351Ter)	GLB1	Pathogenic	criteria provided, multiple submitters, no conflicts
804285	NM_002109.6(HARS1):c.616G>T (p.Asp206Tyr)	HARS1	Pathogenic	criteria provided, single submitter
804286	NM_002109.6(HARS1):c.730delG	HARS1	Pathogenic	criteria provided, single submitter
804287	NM_002109.6(HARS1):c.910_912dup (p.Leu305dup)	HARS1	Pathogenic	criteria provided, single submitter
979212	NM_032756.4(HPDL):c.149G>A (p.Gly50Asp)	HPDL	Pathogenic	criteria provided, multiple submitters, no conflicts
1027530	NM_002617.4(PEX10):c.496del (p.Val166fs)	PEX10	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1027427	NM_001166114.2(PNPLA6):c.43dup (p.Ala15fs)	PNPLA6	Pathogenic	criteria provided, single submitter
445922	NM_007055.4(POLR3A):c.1909+22G>A	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
56210	NM_000310.4(PPT1):c.665T>C (p.Leu222Pro)	PPT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1526041	NM_003119.4(SPG7):c.1861C>T (p.Gln621Ter)	SPG7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
215218	NM_003119.4(SPG7):c.2228T>C (p.Ile743Thr)	SPG7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1027456	NM_001032221.6(STXBP1):c.434A>G (p.Tyr145Cys)	STXBP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
191238	NM_001032221.6(STXBP1):c.874C>T (p.Arg292Cys)	STXBP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1027531	NM_182961.4(SYNE1):c.706C>T (p.Arg236Ter)	SYNE1	Pathogenic	criteria provided, multiple submitters, no conflicts
1027439	NM_006796.3(AFG3L2):c.1712T>G (p.Val571Gly)	AFG3L2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 157 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SACS	Orphanet:98	Autosomal recessive spastic ataxia of Charlevoix-Saguenay
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
SCN8A	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
SCN8A	Orphanet:306	Self-limited infantile epilepsy
SCN8A	Orphanet:352582	Familial infantile myoclonic epilepsy
SCN8A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SPG11	Orphanet:2822	Autosomal recessive spastic paraplegia type 11
SPG11	Orphanet:300605	Juvenile amyotrophic lateral sclerosis
SPG11	Orphanet:466775	Autosomal recessive Charcot-Marie-Tooth disease type 2X
SPAST	Orphanet:100985	Autosomal dominant spastic paraplegia type 4
SPG7	Orphanet:35689	Primary lateral sclerosis
SPG7	Orphanet:99013	Spastic paraplegia type 7
SPTAN1	Orphanet:697160	Infantile epileptic spasms syndrome
STXBP1	Orphanet:495818	9q33.3q34.11 microdeletion syndrome
STXBP1	Orphanet:599373	STXBP1-related encephalopathy
WFS1	Orphanet:3463	Wolfram syndrome
WFS1	Orphanet:411590	Wolfram-like syndrome
WFS1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
WFS1	Orphanet:98991	Early-onset nuclear cataract
CACNA1A	Orphanet:2131	Alternating hemiplegia of childhood
CACNA1A	Orphanet:2382	Lennox-Gastaut syndrome
CACNA1A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
CACNA1A	Orphanet:569	Familial or sporadic hemiplegic migraine
CACNA1A	Orphanet:71518	Benign paroxysmal torticollis of infancy
CACNA1A	Orphanet:97	Familial paroxysmal ataxia
CACNA1A	Orphanet:98758	Spinocerebellar ataxia type 6
CACNA1G	Orphanet:458803	Spinocerebellar ataxia type 42
CACNB4	Orphanet:211067	Episodic ataxia type 5
CACNB4	Orphanet:307	Juvenile myoclonic epilepsy
ELOVL4	Orphanet:1955	Spinocerebellar ataxia type 34
ELOVL4	Orphanet:352333	Congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome
ELOVL4	Orphanet:827	Stargardt disease
PUM1	Orphanet:589515	PUM1-associated developmental disability-ataxia-seizure syndrome
PUM1	Orphanet:642747	PUM1-related cerebellar ataxia
PNPLA6	Orphanet:1173	Cerebellar ataxia-hypogonadism syndrome
PNPLA6	Orphanet:1180	Ataxia-hypogonadism-choroidal dystrophy syndrome
PNPLA6	Orphanet:139480	Autosomal recessive spastic paraplegia type 39
PNPLA6	Orphanet:2377	Laurence-Moon syndrome
PNPLA6	Orphanet:3363	Trichomegaly-retina pigmentary degeneration-dwarfism syndrome
EXOSC8	Orphanet:2254	Pontocerebellar hypoplasia type 1
SYNE2	Orphanet:98853	Autosomal dominant Emery-Dreifuss muscular dystrophy
SYNE1	Orphanet:319332	Autosomal recessive myogenic arthrogryposis multiplex congenita
SYNE1	Orphanet:88644	Autosomal recessive ataxia, Beauce type

Cohort genes → proteins

65 cohort genes, 63 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	65

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SACS	HGNC:10519	ENSG00000151835	Q9NZJ4	Sacsin	clinvar
SCN2A	HGNC:10588	ENSG00000136531	Q99250	Sodium channel protein type 2 subunit alpha	clinvar
SCN8A	HGNC:10596	ENSG00000196876	Q9UQD0	Sodium channel protein type 8 subunit alpha	clinvar
SPG11	HGNC:11226	ENSG00000104133	Q96JI7	Spatacsin	clinvar
SPAST	HGNC:11233	ENSG00000021574	Q9UBP0	Spastin	clinvar
SPG7	HGNC:11237	ENSG00000197912	Q9UQ90	Mitochondrial inner membrane m-AAA protease component paraplegin	clinvar
SPTAN1	HGNC:11273	ENSG00000197694	Q13813	Spectrin alpha chain, non-erythrocytic 1	clinvar
STXBP1	HGNC:11444	ENSG00000136854	P61764	Syntaxin-binding protein 1	clinvar
WFS1	HGNC:12762	ENSG00000109501	O76024	Wolframin	clinvar
CACNA1A	HGNC:1388	ENSG00000141837	O00555	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	clinvar
CACNA1G	HGNC:1394	ENSG00000006283	O43497	Voltage-dependent T-type calcium channel subunit alpha-1G	clinvar
CACNB4	HGNC:1404	ENSG00000182389	O00305	Voltage-dependent L-type calcium channel subunit beta-4	clinvar
ELOVL4	HGNC:14415	ENSG00000118402	Q9GZR5	Very long chain fatty acid elongase 4	clinvar
PUM1	HGNC:14957	ENSG00000134644	Q14671	Pumilio homolog 1	clinvar
PNPLA6	HGNC:16268	ENSG00000032444	Q8IY17	Patatin-like phospholipase domain-containing protein 6	clinvar
EXOSC8	HGNC:17035	ENSG00000120699	Q96B26	Exosome complex component RRP43	clinvar
SYNE2	HGNC:17084	ENSG00000054654	Q8WXH0	Nesprin-2	clinvar
SYNE1	HGNC:17089	ENSG00000131018	Q8NF91	Nesprin-1	clinvar
GJC2	HGNC:17494	ENSG00000198835	Q5T442	Gap junction gamma-2 protein	clinvar
TTBK2	HGNC:19141	ENSG00000128881	Q6IQ55	Tau-tubulin kinase 2	clinvar
LYST	HGNC:1968	ENSG00000143669	Q99698	Lysosomal-trafficking regulator	clinvar
COQ4	HGNC:19693	ENSG00000167113	Q9Y3A0	Ubiquinone biosynthesis protein COQ4 homolog, mitochondrial	clinvar
CCDC88C	HGNC:19967	ENSG00000015133	Q9P219	Protein Daple	clinvar
CLN6	HGNC:2077	ENSG00000128973	Q9NWW5	Ceroid-lipofuscinosis neuronal protein 6	clinvar
TUBB3	HGNC:20772	ENSG00000258947	Q13509	Tubulin beta-3 chain	clinvar
FA2H	HGNC:21197	ENSG00000103089	Q7L5A8	Fatty acid 2-hydroxylase	clinvar
SLC25A46	HGNC:25198	ENSG00000164209	Q96AG3	Mitochondrial outer membrane protein SLC25A46	clinvar
AHDC1	HGNC:25230	ENSG00000126705	Q5TGY3	Transcription factor Gibbin	clinvar
C19orf12	HGNC:25443	ENSG00000131943	Q9NSK7	Protein C19orf12	clinvar
MTPAP	HGNC:25532	ENSG00000107951	Q9NVV4	Poly(A) RNA polymerase, mitochondrial	clinvar
DARS2	HGNC:25538	ENSG00000117593	Q6PI48	Aspartate–tRNA ligase, mitochondrial	clinvar
CYP7B1	HGNC:2652	ENSG00000172817	O75881	Cytochrome P450 7B1	clinvar
DAB1	HGNC:2661	ENSG00000173406	O75553	Disabled homolog 1	clinvar
HPDL	HGNC:28242	ENSG00000186603	Q96IR7	4-hydroxyphenylpyruvate dioxygenase-like protein	clinvar
TMEM67	HGNC:28396	ENSG00000164953	Q5HYA8	Meckelin	clinvar
CEP290	HGNC:29021	ENSG00000198707	O15078	Centrosomal protein of 290 kDa	clinvar
DNMT1	HGNC:2976	ENSG00000130816	P26358	DNA (cytosine-5)-methyltransferase 1	clinvar
PIK3R5	HGNC:30035	ENSG00000141506	Q8WYR1	Phosphoinositide 3-kinase regulatory subunit 5	clinvar
POLR3A	HGNC:30074	ENSG00000148606	O14802	DNA-directed RNA polymerase III subunit RPC1	clinvar
SEPSECS	HGNC:30605	ENSG00000109618	Q9HD40	O-phosphoseryl-tRNA(Sec) selenium transferase	clinvar
AFG3L2	HGNC:315	ENSG00000141385	Q9Y4W6	Mitochondrial inner membrane m-AAA protease component AFG3L2	clinvar
ERCC4	HGNC:3436	ENSG00000175595	Q92889	DNA repair endonuclease XPF	clinvar
FAT2	HGNC:3596	ENSG00000086570	Q9NYQ8	Protocadherin Fat 2	clinvar
GALC	HGNC:4115	ENSG00000054983	P54803	Galactocerebrosidase	clinvar
GLB1	HGNC:4298	ENSG00000170266	P16278	Beta-galactosidase	clinvar
SETX	HGNC:445	ENSG00000107290	Q7Z333	Helicase senataxin	clinvar
AMACR	HGNC:451	ENSG00000242110	Q9UHK6	Alpha-methylacyl-CoA racemase	clinvar
AMPD2	HGNC:469	ENSG00000116337	Q01433	AMP deaminase 2	clinvar
HARS1	HGNC:4816	ENSG00000170445	P12081	Histidine–tRNA ligase, cytoplasmic	clinvar
FLNC-AS1	HGNC:53474	ENSG00000242902		FLNC antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SACS	Sacsin	Co-chaperone which acts as a regulator of the Hsp70 chaperone machinery and may be involved in the processing of other ataxia-linked proteins.
SCN2A	Sodium channel protein type 2 subunit alpha	Mediates the voltage-dependent sodium ion permeability of excitable membranes.
SCN8A	Sodium channel protein type 8 subunit alpha	Pore-forming subunit of a voltage-gated sodium channel complex assuming opened or closed conformations in response to the voltage difference across membranes and through which sodium ions selectively pass along their electrochemical gradie…
SPG11	Spatacsin	May play a role in neurite plasticity by maintaining cytoskeleton stability and regulating synaptic vesicle transport.
SPAST	Spastin	ATP-dependent microtubule severing protein that specifically recognizes and cuts microtubules that are polyglutamylated.
SPG7	Mitochondrial inner membrane m-AAA protease component paraplegin	Catalytic component of the m-AAA protease, a protease that plays a key role in proteostasis of inner mitochondrial membrane proteins, and which is essential for axonal and neuron development.
SPTAN1	Spectrin alpha chain, non-erythrocytic 1	Fodrin, which seems to be involved in secretion, interacts with calmodulin in a calcium-dependent manner and is thus candidate for the calcium-dependent movement of the cytoskeleton at the membrane.
STXBP1	Syntaxin-binding protein 1	Participates in the regulation of synaptic vesicle docking and fusion through interaction with GTP-binding proteins.
WFS1	Wolframin	Participates in the regulation of cellular Ca(2+) homeostasis, at least partly, by modulating the filling state of the endoplasmic reticulum Ca(2+) store.
CACNA1A	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp…
CACNA1G	Voltage-dependent T-type calcium channel subunit alpha-1G	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp…
CACNB4	Voltage-dependent L-type calcium channel subunit beta-4	The beta subunit of voltage-dependent calcium channels contributes to the function of the calcium channel by increasing peak calcium current, shifting the voltage dependencies of activation and inactivation, modulating G protein inhibition…
ELOVL4	Very long chain fatty acid elongase 4	Catalyzes the first and rate-limiting reaction of the four reactions that constitute the long-chain fatty acids elongation cycle.
PUM1	Pumilio homolog 1	Sequence-specific RNA-binding protein that acts as a post-transcriptional repressor by binding the 3’-UTR of mRNA targets.
PNPLA6	Patatin-like phospholipase domain-containing protein 6	Phospholipase B that deacylates intracellular phosphatidylcholine (PtdCho), generating glycerophosphocholine (GroPtdCho).
EXOSC8	Exosome complex component RRP43	Non-catalytic component of the RNA exosome complex which has 3’->5’ exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events.
SYNE2	Nesprin-2	Multi-isomeric modular protein which forms a linking network between organelles and the actin cytoskeleton to maintain the subcellular spatial organization.
SYNE1	Nesprin-1	Multi-isomeric modular protein which forms a linking network between organelles and the actin cytoskeleton to maintain the subcellular spatial organization.
GJC2	Gap junction gamma-2 protein	One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.
TTBK2	Tau-tubulin kinase 2	Serine/threonine kinase that acts as a key regulator of ciliogenesis: controls the initiation of ciliogenesis by binding to the distal end of the basal body and promoting the removal of CCP110, which caps the mother centriole, leading to t…
LYST	Lysosomal-trafficking regulator	Adapter protein that regulates and/or fission of intracellular vesicles such as lysosomes.
COQ4	Ubiquinone biosynthesis protein COQ4 homolog, mitochondrial	Lyase that catalyzes the C1-decarboxylation of 4-hydroxy-3-methoxy-5-(all-trans-decaprenyl)benzoic acid into 2-methoxy-6-(all-trans-decaprenyl)phenol during ubiquinone biosynthesis.
CCDC88C	Protein Daple	Required for activation of guanine nucleotide-binding proteins (G-proteins) during non-canonical Wnt signaling.
TUBB3	Tubulin beta-3 chain	Tubulin is the major constituent of microtubules, protein filaments consisting of alpha- and beta-tubulin heterodimers.
FA2H	Fatty acid 2-hydroxylase	Catalyzes the hydroxylation of free fatty acids at the C-2 position to produce 2-hydroxy fatty acids, which are building blocks of sphingolipids and glycosphingolipids common in neural tissue and epidermis.
SLC25A46	Mitochondrial outer membrane protein SLC25A46	Transmembrane protein of the mitochondrial outer membrane that controls mitochondrial organization.
AHDC1	Transcription factor Gibbin	Transcription factor required for the proper patterning of the epidermis, which plays a key role in early epithelial morphogenesis.
MTPAP	Poly(A) RNA polymerase, mitochondrial	Polymerase that creates the 3’ poly(A) tail of mitochondrial transcripts.
DARS2	Aspartate–tRNA ligase, mitochondrial	Catalyzes the attachment of aspartate to tRNA(Asp) in a two-step reaction: aspartate is first activated by ATP to form Asp-AMP and then transferred to the acceptor end of tRNA(Asp).
CYP7B1	Cytochrome P450 7B1	A cytochrome P450 monooxygenase involved in the metabolism of endogenous oxysterols and steroid hormones, including neurosteroids.
DAB1	Disabled homolog 1	Signaling adapter of the reelin-mediated signaling pathway, which regulates the migration and differentiation of postmitotic neurons during brain development.
HPDL	4-hydroxyphenylpyruvate dioxygenase-like protein	Iron-dependent dioxygenase that catalyzes the conversion of 4-hydroxyphenylpyruvate (4-HPPA) to 4-hydroxymandelate (4-HMA) in the mitochondria, one of the steps in the biosynthesis of coenzyme Q10 from tyrosine.
TMEM67	Meckelin	Required for ciliary structure and function.
CEP290	Centrosomal protein of 290 kDa	Involved in early and late steps in cilia formation.
DNMT1	DNA (cytosine-5)-methyltransferase 1	DNA methyltransferase that methylates CpG residues.
PIK3R5	Phosphoinositide 3-kinase regulatory subunit 5	Regulatory subunit of the PI3K gamma complex.
POLR3A	DNA-directed RNA polymerase III subunit RPC1	Catalytic core component of RNA polymerase III (Pol III), a DNA-dependent RNA polymerase which synthesizes small non-coding RNAs using the four ribonucleoside triphosphates as substrates.
SEPSECS	O-phosphoseryl-tRNA(Sec) selenium transferase	Converts O-phosphoseryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec) required for selenoprotein biosynthesis.
AFG3L2	Mitochondrial inner membrane m-AAA protease component AFG3L2	Catalytic component of the m-AAA protease, a protease that plays a key role in proteostasis of inner mitochondrial membrane proteins, and which is essential for axonal and neuron development.
ERCC4	DNA repair endonuclease XPF	Catalytic component of a structure-specific DNA repair endonuclease responsible for the 5-prime incision during DNA repair, and which is essential for nucleotide excision repair (NER) and interstrand cross-link (ICL) repair.
FAT2	Protocadherin Fat 2	Involved in the regulation of cell migration.
GALC	Galactocerebrosidase	Hydrolyzes the galactose ester bonds of glycolipids such as galactosylceramide and galactosylsphingosine.
GLB1	Beta-galactosidase	Cleaves beta-linked terminal galactosyl residues from gangliosides, glycoproteins, and glycosaminoglycans.
SETX	Helicase senataxin	ATP-dependent 5’->3’ DNA/RNA helicase that preferentially unwinds RNA substrates over DNA, playing a crucial role in resolving R-loops and promoting transcription termination.
AMACR	Alpha-methylacyl-CoA racemase	Catalyzes the interconversion of (R)- and (S)-stereoisomers of alpha-methyl-branched-chain fatty acyl-CoA esters.
AMPD2	AMP deaminase 2	AMP deaminase plays a critical role in energy metabolism.
HARS1	Histidine–tRNA ligase, cytoplasmic	Catalyzes the ATP-dependent ligation of histidine to the 3’-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (His-AMP).
APOB	Apolipoprotein B-100	Apolipoprotein B is a major protein constituent of chylomicrons (apo B-48), LDL (apo B-100) and VLDL (apo B-100).
ITPR1	Inositol 1,4,5-trisphosphate-gated calcium channel ITPR1	Inositol 1,4,5-trisphosphate-gated calcium channel that, upon inositol 1,4,5-trisphosphate binding, mediates calcium release from the endoplasmic reticulum (ER).
KCNMA1	Calcium-activated potassium channel subunit alpha-1	Potassium channel activated by both membrane depolarization or increase in cytosolic Ca(2+) that mediates export of K(+).

Protein-family classification

Druggable: 22 · Difficult: 12 · Unknown: 31 · Druggable fraction: 0.34

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	6	10.3×	2e-04
Enzyme (other)	12	2.2×	0.028
Scaffold/PPI	6	1.6×	0.460
Phosphatase	1	1.3×	0.867
Protease	2	1.1×	0.867
Other/Unknown	31	0.8×	0.926
Transcription factor	6	0.8×	0.926
Kinase	1	0.4×	0.926

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SACS	Other/Unknown	no		Ubiquitin-like_dom, DnaJ_domain, HEPN_dom
SCN2A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
SCN8A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
SPG11	Other/Unknown	no		Spatacsin, Spatacsin_C_dom
SPAST	Enzyme (other)	yes	5.6.1.1	AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS
SPG7	Protease	yes	3.4.24.B18	Peptidase_M41, AAA+_ATPase, ATPase_AAA_core
SPTAN1	Scaffold/PPI	no		SH3_domain, Spectrin_repeat, EF_hand_dom
STXBP1	Other/Unknown	no		Sec1-like, Sec1-like_dom2, Sec1-like_sf
WFS1	Other/Unknown	no		TPR-like_helical_dom_sf, Wolframin, Wolframin_fam
CACNA1A	Ion channel	yes		VDCCAlpha1, CACNA1A, Ion_trans_dom
CACNA1G	Ion channel	yes		VDCCAlpha1, VDCC_T_a1, Ion_trans_dom
CACNB4	Scaffold/PPI	no		VDCC_L_bsu, SH3_domain, GK/Ca_channel_bsu
ELOVL4	Other/Unknown	no		ELO_fam, ELO_CS, ELOVL4
PUM1	Transcription factor	no		Pumilio_RNA-bd_rpt, ARM-like, ARM-type_fold
PNPLA6	Other/Unknown	no		cNMP-bd_dom, LysoPLipase_patatin_CS, PNPLA_dom
EXOSC8	Scaffold/PPI	no		ExoRNase_PH_dom1, ExoRNase_PH_dom2, Ribosomal_Su5_D2-typ_SF
SYNE2	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat
SYNE1	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat
GJC2	Other/Unknown	no		Connexin, Connexin_N, Connexin_CS
TTBK2	Kinase	yes	2.7.11.26	Prot_kinase_dom, Kinase-like_dom_sf, Protein_kinase_ATP_BS
LYST	Scaffold/PPI	no		BEACH_dom, WD40_rpt, PH-like_dom_sf
COQ4	Other/Unknown	no		Coq4, Coq4_euk
CCDC88C	Other/Unknown	no		CH_dom, CH_dom_sf, HOOK_N
CLN6	Other/Unknown	no		CLN6
TUBB3	Other/Unknown	no		Tubulin, Beta_tubulin, Tubulin_FtsZ_GTPase
FA2H	Enzyme (other)	yes	1.14.18.6	Cyt_B5-like_heme/steroid-bd, Fatty_acid_hydroxylase, Scs7
SLC25A46	Other/Unknown	no		MCP_transmembrane, MCP_dom_sf, SLC25A46
AHDC1	Other/Unknown	no		DUF4683, AHDC1
C19orf12	Other/Unknown	no		C19orf12
MTPAP	Enzyme (other)	yes	2.7.7.19	PAP_assoc, RL, NT_sf
DARS2	Enzyme (other)	yes	6.1.1.12	Asp/Asn-tRNA-synth_IIb, GAD-like_sf, Aa-tRNA-synt_II
CYP7B1	Enzyme (other)	yes	1.14.14.29	Cyt_P450, Cyt_P450_E_grp-IV, Cyt_P450_CYP7A1-type
DAB1	Other/Unknown	no		PTB/PI_dom, PH-like_dom_sf, DAB1/2_SBM
HPDL	Other/Unknown	no		4OHPhenylPyrv_dOase, Glyas_Bleomycin-R_OHBP_Dase, VOC_core
TMEM67	Other/Unknown	no		Growth_fac_rcpt_cys_sf, Meckelin
CEP290	Other/Unknown	no		Cep290, Cep209_CC5
DNMT1	Transcription factor	no	2.1.1.37	BAH_dom, C5_MeTfrase, Znf_CXXC
PIK3R5	Other/Unknown	no		PIK3R5/6
POLR3A	Other/Unknown	no		RNA_pol_asu, RNA_pol_N, RNA_pol_Rpb1_3
SEPSECS	Enzyme (other)	yes	2.9.1.2	SepSecS/SepCysS, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase
AFG3L2	Protease	yes	3.4.24.B18	Peptidase_M41, AAA+_ATPase, ATPase_AAA_core
ERCC4	Other/Unknown	no		ERCC4_domain, XPF, RuvA_2-like
FAT2	Other/Unknown	no		EGF, Laminin_G, EGF-like_Ca-bd_dom
GALC	Enzyme (other)	yes	3.2.1.46	Glyco_hydro_59, Aldolase_TIM, GH_hydrolase_sf
GLB1	Other/Unknown	no		Glycoside_Hdrlase_35, Galactose-bd-like_sf, GH_hydrolase_sf
SETX	Other/Unknown	no		P-loop_NTPase, DNA2/NAM7_AAA_11, DNA2/NAM7-like_C
AMACR	Enzyme (other)	yes	5.1.99.4	CoA-Trfase_fam_III, CoA-Trfase_III_dom_1_sf, CoA-Trfase_III_dom3_sf
AMPD2	Enzyme (other)	yes	3.5.4.6	AMPD, A/AMP_deam_AS, Metal_Hydrolase
HARS1	Enzyme (other)	yes	6.1.1.21	WHEP-TRS_dom, Anticodon-bd, HisRS/HisZ
FLNC-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

59 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)	65
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	8
right uterine tube	8
granulocyte	6
monocyte	6
middle temporal gyrus	5
secondary oocyte	5
lateral nuclear group of thalamus	5
calcaneal tendon	4
oocyte	4
right hemisphere of cerebellum	4
C1 segment of cervical spinal cord	4
leukocyte	4
jejunal mucosa	4
cerebellar vermis	3
cortical plate	3
primordial germ cell in gonad	3
sural nerve	3
cerebellar cortex	3
cerebellar hemisphere	3
right frontal lobe	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SACS	286	ubiquitous	marker	Brodmann (1909) area 23, middle frontal gyrus, frontal pole
SCN2A	187	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, cerebellar vermis
SCN8A	194	ubiquitous	marker	Brodmann (1909) area 23, middle temporal gyrus, postcentral gyrus
SPG11	295	ubiquitous	marker	bronchial epithelial cell, granulocyte, calcaneal tendon
SPAST	284	ubiquitous	marker	cortical plate, oocyte, secondary oocyte
SPG7	302	ubiquitous	marker	primordial germ cell in gonad, sural nerve, left lobe of thyroid gland
SPTAN1	293	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
STXBP1	287	ubiquitous	marker	middle temporal gyrus, lateral nuclear group of thalamus, Brodmann (1909) area 23
WFS1	280	ubiquitous	marker	right ovary, left ovary, body of uterus
CACNA1A	237	broad	marker	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex
CACNA1G	194	broad	yes	lateral nuclear group of thalamus, right hemisphere of cerebellum, right frontal lobe
CACNB4	201	broad	marker	cerebellar vermis, lateral nuclear group of thalamus, primary visual cortex
ELOVL4	228	ubiquitous	marker	upper leg skin, upper arm skin, mammalian vulva
PUM1	303	ubiquitous	marker	dorsal motor nucleus of vagus nerve, CA1 field of hippocampus, germinal epithelium of ovary
PNPLA6	276	ubiquitous	marker	granulocyte, metanephros cortex, upper lobe of left lung
EXOSC8	298	ubiquitous	marker	ventricular zone, ganglionic eminence, right uterine tube
SYNE2	284	ubiquitous	marker	ventricular zone, skeletal muscle tissue of biceps brachii, ganglionic eminence
SYNE1	275	ubiquitous	marker	cerebellar hemisphere, right hemisphere of cerebellum, calcaneal tendon
GJC2	181	tissue_specific	yes	C1 segment of cervical spinal cord, spinal cord, inferior vagus X ganglion
TTBK2	275	ubiquitous	marker	lateral nuclear group of thalamus, Brodmann (1909) area 23, pons
LYST	278	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
COQ4	254	ubiquitous	marker	right uterine tube, olfactory segment of nasal mucosa, adenohypophysis
CCDC88C	220	ubiquitous	marker	right uterine tube, granulocyte, olfactory segment of nasal mucosa
CLN6	139	ubiquitous	marker	monocyte, leukocyte, bone marrow
TUBB3	144	ubiquitous	marker	cortical plate, ganglionic eminence, embryo
FA2H	213	broad	marker	C1 segment of cervical spinal cord, spinal cord, corpus callosum
SLC25A46	290	ubiquitous	marker	sperm, secondary oocyte, oocyte
AHDC1	232	ubiquitous	marker	paraflocculus, Brodmann (1909) area 10, frontal pole
C19orf12	253	ubiquitous	marker	endothelial cell, kidney epithelium, epithelial cell of pancreas
MTPAP	276	ubiquitous	marker	oocyte, secondary oocyte, gingival epithelium

Protein interactions among cohort

Intra-cohort edges: 40.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNMT1	7,179
TUBB3	6,797
PUM1	5,826
APOB	5,244
POLR3A	4,915
AFG3L2	4,260
SPG7	3,970
ITPR1	3,483
WFS1	3,409
SPAST	3,393

Intra-cohort edges

A	B	Sources
AFG3L2	MTPAP	string_interaction
AFG3L2	SPG7	string_interaction
ARSA	GALC	string_interaction
ARSA	GLB1	string_interaction
C19orf12	FA2H	string_interaction
C19orf12	PLA2G6	string_interaction
C19orf12	PNPLA6	string_interaction
C19orf12	SPG11	string_interaction
CACNA1A	CACNB4	biogrid_interaction
CEP290	MKS1	string_interaction
CEP290	TMEM67	string_interaction
CLN6	PPT1	string_interaction
CYP7B1	PNPLA6	string_interaction
CYP7B1	SPG7	string_interaction
ELOVL4	FA2H	biogrid_interaction, intact
FA2H	PLA2G6	string_interaction
FA2H	PNPLA6	string_interaction
FA2H	SPG11	string_interaction
FA2H	SPG7	string_interaction
GALC	GLB1	string_interaction
GJC2	PNPLA6	string_interaction
GJC2	SPG11	string_interaction
GJC2	SPG7	string_interaction
GLB1	NAGLU	string_interaction
KIF1A	WFS1	intact
KIF1C	LYST	biogrid_interaction, intact
KIF1C	SPAST	string_interaction
KIF1C	SPG7	string_interaction
MKS1	SYNE2	biogrid_interaction
MKS1	TMEM67	string_interaction
PNPLA6	SPG11	string_interaction
PNPLA6	SPG7	string_interaction
PUM1	WFS1	intact
SCN2A	STXBP1	string_interaction
SETX	SPG11	string_interaction
SPAST	SPG11	string_interaction
SPG11	SPG7	string_interaction
SPTAN1	STXBP1	string_interaction
SYNE1	SYNE2	string_interaction
SYNE2	TMEM67	biogrid_interaction, string_interaction

Structural data

PDB: 37 · AlphaFold-only: 26 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNMA1	Q12791	36
POLR3A	O14802	29
TUBB3	Q13509	28
DNMT1	P26358	27
KIF1A	Q12756	21
PUM1	Q14671	15
ERCC4	Q92889	13
ATP7B	P35670	13
HARS1	P12081	10
ARSA	P15289	10
EXOSC8	Q96B26	8
GLB1	P16278	8
APOB	P04114	8
SACS	Q9NZJ4	7
SCN8A	Q9UQD0	7
SPAST	Q9UBP0	7
SPTAN1	Q13813	7
SEPSECS	Q9HD40	7
TTBK2	Q6IQ55	6
SCN2A	Q99250	5
CACNA1A	O00555	4
AMPD2	Q01433	4
SPG11	Q96JI7	3
SYNE2	Q8WXH0	3
SYNE1	Q8NF91	3
CACNA1G	O43497	2
AFG3L2	Q9Y4W6	2
KIF1C	O43896	2
SPG7	Q9UQ90	1
STXBP1	P61764	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AMACR	Q9UHK6	95.79
GALC	P54803	94.56
CYP7B1	O75881	91.98
HPDL	Q96IR7	91.45
COQ4	Q9Y3A0	88.56
ATP1A2	P50993	88.25
PLA2G6	O60733	86.16
CLN6	Q9NWW5	85.86
FA2H	Q7L5A8	85.53
ELOVL4	Q9GZR5	84.53
PEX10	O60683	82.81
ATP2B3	Q16720	74.57
MKS1	Q9NXB0	74.05
WFS1	O76024	73.85
PIK3R5	Q8WYR1	71.39
PNPLA6	Q8IY17	69.75
GJC2	Q5T442	68.50
CCDC88C	Q9P219	65.69
CEP290	O15078	60.90
C19orf12	Q9NSK7	59.50
DAB1	O75553	59.20
SETX	Q7Z333	52.93
AHDC1	Q5TGY3	38.82
LYST	Q99698
FAT2	Q9NYQ8
ITPR1	Q14643

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 316. Enrichment computed across 65 evidence-associated genes (54 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 54 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Platelet homeostasis	4	20.6×	0.010	APOB, ITPR1, KCNMA1, ATP2B3
Muscle contraction	6	8.6×	0.010	SCN2A, SCN8A, CACNA1G, ITPR1, ATP1A2, ATP2B3
Cardiac conduction	5	10.1×	0.014	SCN2A, SCN8A, ITPR1, ATP1A2, ATP2B3
Mucopolysaccharidoses	2	70.5×	0.026	GLB1, NAGLU
Interaction between L1 and Ankyrins	3	20.5×	0.026	SCN2A, SCN8A, SPTAN1
Presynaptic depolarization and calcium channel opening	2	35.2×	0.034	CACNA1A, CACNB4
Ubiquinol biosynthesis	2	32.5×	0.034	COQ4, HPDL
Nitric oxide stimulates guanylate cyclase	2	30.2×	0.034	ITPR1, KCNMA1
Diseases of carbohydrate metabolism	2	30.2×	0.034	GLB1, NAGLU
Glycosphingolipid catabolism	3	16.3×	0.034	GALC, GLB1, ARSA
NCAM signaling for neurite out-growth	3	15.1×	0.034	SPTAN1, CACNA1G, CACNB4
Regulation of insulin secretion	3	12.2×	0.034	STXBP1, CACNA1A, ITPR1
L1CAM interactions	4	8.9×	0.034	SCN2A, SCN8A, SPTAN1, TUBB3
Anchoring of the basal body to the plasma membrane	4	8.4×	0.034	TTBK2, TMEM67, CEP290, MKS1
Cilium Assembly	4	8.1×	0.034	TUBB3, TMEM67, CEP290, MKS1
Axon guidance	6	5.0×	0.034	SCN2A, SCN8A, SPTAN1, CACNA1G, CACNB4, TUBB3
Nervous system development	6	4.8×	0.034	SCN2A, SCN8A, SPTAN1, CACNA1G, CACNB4, TUBB3
Hemostasis	7	4.7×	0.034	TUBB3, APOB, ITPR1, KCNMA1, KIF1C, ATP2B3, KIF1A
Platelet calcium homeostasis	2	26.4×	0.035	ITPR1, ATP2B3
cGMP effects	2	26.4×	0.035	ITPR1, KCNMA1
Ion transport by P-type ATPases	3	11.5×	0.035	ATP1A2, ATP2B3, ATP7B
Ion homeostasis	3	11.3×	0.035	ITPR1, ATP1A2, ATP2B3
Sensory Perception	4	7.0×	0.035	SCN2A, SPTAN1, APOB, KCNMA1
Processing of SMDT1	2	23.5×	0.042	SPG7, AFG3L2
Kinesins	3	9.9×	0.043	TUBB3, KIF1C, KIF1A
Integration of energy metabolism	3	9.8×	0.043	STXBP1, CACNA1A, ITPR1
Heparan sulfate/heparin (HS-GAG) metabolism	2	20.1×	0.049	GLB1, NAGLU
Mitochondrial calcium ion transport	2	20.1×	0.049	SPG7, AFG3L2
MPS IIIB - Sanfilippo syndrome B	1	211.5×	0.050	NAGLU
Defective CYP7B1 causes SPG5A and CBAS3	1	211.5×	0.050	CYP7B1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 63 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 calcium import into the mitochondrion	2	178.3×	0.013	SPG7, AFG3L2
ganglioside metabolic process	2	133.8×	0.013	CLN6, NAGLU
anterograde neuronal dense core vesicle transport	2	133.8×	0.013	KIF1C, KIF1A
retrograde neuronal dense core vesicle transport	2	107.0×	0.013	KIF1C, KIF1A
cardiac muscle cell action potential involved in contraction	3	33.4×	0.013	SCN2A, SCN8A, CACNA1G
myelination	4	16.0×	0.013	SCN2A, SCN8A, AFG3L2, GALC
protein catabolic process	4	15.1×	0.013	SPG11, CLN6, AFG3L2, PPT1
anterograde axonal transport	3	27.7×	0.013	SPAST, SPG7, KIF1A
mitochondrial protein processing	2	89.2×	0.014	SPG7, AFG3L2
neuromuscular junction development	3	25.1×	0.014	SPG11, CACNB4, AFG3L2
glycosaminoglycan metabolic process	2	76.4×	0.015	CLN6, NAGLU
locomotion involved in locomotory behavior	2	76.4×	0.015	CLN6, SLC25A46
neuronal action potential propagation	2	44.6×	0.042	CACNB4, ATP1A2
calcium import into the mitochondrion	2	38.2×	0.047	AFG3L2, ITPR1
lysosome organization	3	14.6×	0.047	SPG11, CLN6, NAGLU
adult locomotory behavior	3	14.3×	0.047	PUM1, ATP1A2, PPT1
cristae formation	2	33.4×	0.056	SLC25A46, AFG3L2
sodium ion transport	3	12.9×	0.056	SCN2A, SCN8A, ATP1A2
intracellular potassium ion homeostasis	2	31.5×	0.056	KCNMA1, ATP1A2
mitochondrial calcium ion homeostasis	2	31.5×	0.056	C19orf12, AFG3L2
smoothened signaling pathway involved in regulation of secondary heart field cardioblast proliferation	1	267.5×	0.057	MKS1
cell-cell adhesion involved in neuronal-glial interactions involved in cerebral cortex radial glia guided migration	1	267.5×	0.057	DAB1
olfactory cortex development	1	267.5×	0.057	ATP1A2
response to disaccharide	1	267.5×	0.057	NAGLU
epigenetic programming of gene expression	1	267.5×	0.057	DNMT1
cyclic purine nucleotide metabolic process	1	267.5×	0.057	AMPD2
positive regulation of termination of DNA-templated transcription	1	267.5×	0.057	SETX
mitochondrial asparaginyl-tRNA aminoacylation	1	267.5×	0.057	DARS2
cellular response to glutathione	1	267.5×	0.057	AFG3L2
SA node cell to atrial cardiac muscle cell signaling	1	267.5×	0.057	CACNA1G

Therapeutics

Drug target analysis

Approved (phase 4): 10 · Phase ≥3: 11 · Phased (≥1): 13 · Undrugged: 52

Druggability breadth: 36 of 65 evidence-associated genes (55%) 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
SCN2A	BEPRIDIL
SCN8A	IMIPRAMINE
CACNA1A	NIMODIPINE
CACNA1G	NIMODIPINE
CACNB4	NIMODIPINE
TUBB3	COLCHICINE
DNMT1	DECITABINE
GLB1	MIGALASTAT
KCNMA1	CANNABIDIOL
ATP1A2	OMEPRAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN2A	99	4
SCN8A	25	4
TUBB3	21	4
CACNA1G	8	4
DNMT1	6	4
ATP1A2	5	4
PIK3R5	4	3
CACNA1A	2	4
CACNB4	2	4
KCNMA1	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	SCN2A
DIBUCAINE	4	SCN2A
ARTICAINE	4	SCN2A
BUPIVACAINE	4	SCN2A
IMIPRAMINE	4	SCN2A, SCN8A
DROPERIDOL	4	SCN2A
DICYCLOMINE	4	SCN2A
TETRABENAZINE	4	SCN2A
PHENIRAMINE	4	SCN2A
PRILOCAINE	4	SCN2A
PROPOXYCAINE	4	SCN2A
PROPARACAINE	4	SCN2A
HEXYLCAINE	4	SCN2A
PRAMOXINE	4	SCN2A
BENOXINATE	4	SCN2A
QUINIDINE	4	SCN2A
FELODIPINE	4	SCN2A
PHENYTOIN	4	SCN2A
QUININE	4	SCN2A
NISOLDIPINE	4	SCN2A
NIFEDIPINE	4	SCN2A, SCN8A
PRAZOSIN	4	SCN2A
DILTIAZEM	4	SCN2A, SCN8A
PRENYLAMINE	4	SCN2A
COCAINE	4	SCN2A
TRIFLUOPERAZINE	4	SCN2A
CINNARIZINE	4	SCN2A
THIORIDAZINE	4	SCN2A
ETIDOCAINE	4	SCN2A
CHLORPHENIRAMINE	4	SCN2A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 20.

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

Symbol	Assays	Type breakdown
TUBB3	1,781	Binding:1741, Functional:34, ADMET:6
DNMT1	233	Binding:229, Functional:3, ADMET:1
SCN2A	203	Binding:172, Functional:20, ADMET:10, Toxicity:1
SCN8A	173	Binding:148, Functional:16, ADMET:7, Toxicity:2
GLB1	124	Binding:123, ADMET:1
CACNA1G	105	Binding:91, Functional:11, ADMET:2, Toxicity:1
KCNMA1	94	Binding:91, Functional:2, Toxicity:1
TTBK2	56	Binding:56
ATP1A2	49	Binding:49
PLA2G6	47	Binding:47
ERCC4	28	Binding:28
CACNA1A	19	Binding:18, Functional:1
CACNB4	13	Binding:13
ITPR1	13	Binding:12, Functional:1
PIK3R5	8	Binding:8
SPTAN1	7	Binding:7
HARS1	5	Binding:5
PPT1	5	Binding:5
AMPD2	4	Binding:4
ARSA	4	Binding:3, Functional:1
NAGLU	4	Binding:4
AFG3L2	3	Binding:3
GALC	3	Binding:2, Functional:1
FA2H	2	Binding:2
CYP7B1	2	ADMET:2
KIF1A	2	Binding:2
SPG11	1	Binding:1
SPAST	1	Binding:1
STXBP1	1	Binding:1
WFS1	1	Binding:1
ELOVL4	1	Binding:1
PUM1	1	Binding:1
PNPLA6	1	Binding:1
CLN6	1	Binding:1
APOB	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SPAST	5.6.1.1	microtubule-severing ATPase
SPG7	3.4.24.B18
TTBK2	2.7.11.26	tau-protein kinase
FA2H	1.14.18.6	4-hydroxysphinganine ceramide fatty acyl 2-hydroxylase
MTPAP	2.7.7.19	polynucleotide adenylyltransferase
DARS2	6.1.1.12	aspartate-tRNA ligase
CYP7B1	1.14.14.29	25/26-hydroxycholesterol 7alpha-hydroxylase
DNMT1	2.1.1.37	DNA (cytosine-5-)-methyltransferase
SEPSECS	2.9.1.2	O-phospho-L-seryl-tRNASec:L-selenocysteinyl-tRNA synthase
AFG3L2	3.4.24.B18
GALC	3.2.1.46	galactosylceramidase
AMACR	5.1.99.4	alpha-methylacyl-CoA racemase
AMPD2	3.5.4.6	AMP deaminase
HARS1	6.1.1.21	histidine-tRNA ligase
NAGLU	3.2.1.50	alpha-N-acetylglucosaminidase
ATP2B3	7.2.2.10	P-type Ca2+ transporter
ATP7B	7.2.2.8, 7.2.2.9	P-type Cu+ transporter, P-type Cu2+ transporter
KIF1A	5.6.1.3	plus-end-directed kinesin ATPase
PLA2G6	3.1.1.4	phospholipase A2
PPT1	3.1.2.2, 3.1.2.22	palmitoyl-CoA hydrolase, palmitoyl[protein] hydrolase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN2A	203
SCN8A	173
CACNA1G	105
TUBB3	1,781
DNMT1	233
GLB1	124

Pharmacogenomics

Cohort genes with a PharmGKB record: 63; 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)
BEPRIDIL	4	SCN2A
DIBUCAINE	4	SCN2A
ARTICAINE	4	SCN2A
BUPIVACAINE	4	SCN2A
IMIPRAMINE	4	SCN2A, SCN8A
DROPERIDOL	4	SCN2A
DICYCLOMINE	4	SCN2A
TETRABENAZINE	4	SCN2A
PHENIRAMINE	4	SCN2A
PRILOCAINE	4	SCN2A
PROPOXYCAINE	4	SCN2A
PROPARACAINE	4	SCN2A
HEXYLCAINE	4	SCN2A
PRAMOXINE	4	SCN2A
BENOXINATE	4	SCN2A
QUINIDINE	4	SCN2A
FELODIPINE	4	SCN2A
PHENYTOIN	4	SCN2A
QUININE	4	SCN2A
NISOLDIPINE	4	SCN2A
NIFEDIPINE	4	SCN2A, SCN8A
PRAZOSIN	4	SCN2A
DILTIAZEM	4	SCN2A, SCN8A
PRENYLAMINE	4	SCN2A
COCAINE	4	SCN2A
TRIFLUOPERAZINE	4	SCN2A
CINNARIZINE	4	SCN2A
THIORIDAZINE	4	SCN2A
ETIDOCAINE	4	SCN2A
CHLORPHENIRAMINE	4	SCN2A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	10	SCN2A, SCN8A, CACNA1A, CACNA1G, CACNB4, TUBB3, DNMT1, GLB1, KCNMA1, ATP1A2
B	Phased (≥1) drug, not yet approved	3	SPTAN1, PIK3R5, PLA2G6
C	Druggable family + PDB, no drug	12	SPAST, SPG7, TTBK2, MTPAP, DARS2, SEPSECS, AFG3L2, AMPD2, HARS1, ARSA (+2 more)
D	Druggable family + AlphaFold only, no drug	5	FA2H, CYP7B1, GALC, AMACR, ITPR1
E	Difficult family or no structure, no drug	35	SACS, SPG11, STXBP1, WFS1, ELOVL4, PUM1, PNPLA6, EXOSC8, SYNE2, SYNE1 (+25 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
C19orf12	0	PLA2G6
GALC	3	GLB1
SACS	0	—
SPG11	1	—
SPAST	1	—
SPG7	0	—
STXBP1	1	—
WFS1	1	—
ELOVL4	1	—
PUM1	1	—
PNPLA6	1	—
EXOSC8	0	—
SYNE2	0	—
SYNE1	0	—
GJC2	0	—
TTBK2	56	—
LYST	0	—
COQ4	0	—
CCDC88C	0	—
CLN6	1	—
FA2H	2	—
SLC25A46	0	—
AHDC1	0	—
MTPAP	0	—
DARS2	0	—
CYP7B1	2	—
DAB1	0	—
HPDL	0	—
TMEM67	0	—
CEP290	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
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT04297891	Not specified	UNKNOWN	Phenotypes, Biomarkers and Pathophysiology in Spastic Ataxias