Autosomal dominant cerebellar ataxia

Summary

Autosomal dominant cerebellar ataxia (MONDO:0020380) is a disease (an umbrella term covering 16 Mondo subtypes) with 10 cohort genes and 51 clinical trials. Top therapeutic interventions include lithium carbonate, troriluzole, and isoxaflutole.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Umbrella term: 16 Mondo subtypes
• Cohort genes: 10
• ClinVar variants: 399
• Clinical trials: 51

Clinical features

Epidemiology

Prevalence records

6 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	2.7	Worldwide	Validated
Point prevalence	1-9 / 100 000	5.6	Europe	Validated
Point prevalence	1-9 / 100 000	3	Netherlands	Validated
Point prevalence	1-9 / 1 000 000	0.9	Italy	Validated
Point prevalence	1-9 / 100 000	5.6	Portugal	Validated
Point prevalence	1-5 / 10 000	12.6	Japan	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant cerebellar ataxia
Mondo ID	MONDO:0020380
OMIM	164400
Orphanet	99
DOID	DOID:1441
SNOMED CT	129609000
UMLS	C4087347
MedGen	1684639
GARD	0004346
NORD	825
Is cancer (heuristic)	no

Also known as: ADCA · Autosomal Dominant Hereditary Ataxia · autosomal dominant spinocerebellar ataxia · cerebellar ataxia, autosomal dominant · Pierre Marie cerebellar ataxia (formerly) · SCA · spinocerebellar ataxia

Data availability: 399 ClinVar variants · 45 cell lines.

Disease family

An umbrella term covering 16 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant cerebellar ataxia

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

Subtypes (16): GRID2-related autosomal dominant spinocerebellar ataxia, spinocerebellar ataxia 27A, spinocerebellar ataxia 9, spinocerebellar ataxia 43, spinocerebellar ataxia 7, autosomal dominant cerebellar ataxia type I, autosomal dominant cerebellar ataxia type III, autosomal dominant cerebellar ataxia type IV, spinocerebellar ataxia 49, spinocerebellar ataxia 48, spinocerebellar ataxia 44, spinocerebellar ataxia 47, spinocerebellar ataxia 50, spinocerebellar ataxia 27B, late-onset, spinocerebellar ataxia 51, spinocerebellar ataxia 52

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

399 retrieved; paginated sample, class counts are floors:

117 conflicting classifications of pathogenicity, 101 uncertain significance, 89 benign/likely benign, 68 benign, 22 likely benign, 1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2627937	NM_130837.3(OPA1):c.460A>T (p.Lys154Ter)	OPA1-AS1	Pathogenic	criteria provided, single submitter
2663893	NM_006133.3(DAGLA):c.2437_2446del (p.Leu813fs)	DAGLA	Likely pathogenic	criteria provided, single submitter
128923	NM_001376.5(DYNC1H1):c.12102+6G>A	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
128930	NM_001376.5(DYNC1H1):c.13181C>T (p.Thr4394Met)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
197458	NM_001376.5(DYNC1H1):c.8478A>G (p.Ala2826=)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210866	NM_001376.5(DYNC1H1):c.13440C>T (p.Ser4480=)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210870	NM_001376.5(DYNC1H1):c.4515G>A (p.Ser1505=)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210873	NM_001376.5(DYNC1H1):c.5985C>T (p.Ala1995=)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210875	NM_001376.5(DYNC1H1):c.7203A>C (p.Lys2401Asn)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239001	NM_001376.5(DYNC1H1):c.5971G>A (p.Asp1991Asn)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
245763	NM_001376.5(DYNC1H1):c.5422C>A (p.Leu1808Ile)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
246234	NM_001376.5(DYNC1H1):c.7420G>A (p.Ala2474Thr)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
285546	NM_001376.5(DYNC1H1):c.7192C>T (p.Arg2398Cys)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
312616	NM_001376.5(DYNC1H1):c.161C>T (p.Ala54Val)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
312618	NM_001376.5(DYNC1H1):c.366T>C (p.Thr122=)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
312621	NM_001376.5(DYNC1H1):c.1861G>A (p.Asp621Asn)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
312623	NM_001376.5(DYNC1H1):c.2211T>A (p.Val737=)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
312624	NM_001376.5(DYNC1H1):c.2672A>G (p.His891Arg)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
312630	NM_001376.5(DYNC1H1):c.5217C>T (p.Ile1739=)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
312635	NM_001376.5(DYNC1H1):c.6339G>A (p.Arg2113=)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
312636	NM_001376.5(DYNC1H1):c.6711G>A (p.Leu2237=)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
312637	NM_001376.5(DYNC1H1):c.7014+11T>A	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
312638	NM_001376.5(DYNC1H1):c.7308G>A (p.Ala2436=)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
312640	NM_001376.5(DYNC1H1):c.8178-12A>T	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
312644	NM_001376.5(DYNC1H1):c.9210G>A (p.Pro3070=)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
312646	NM_001376.5(DYNC1H1):c.10575T>C (p.Arg3525=)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
312647	NM_001376.5(DYNC1H1):c.10752T>C (p.Asn3584=)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
312648	NM_001376.5(DYNC1H1):c.10754+11G>A	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
312652	NM_001376.5(DYNC1H1):c.11460+4G>A	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
312654	NM_001376.5(DYNC1H1):c.11913C>G (p.Pro3971=)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DYNC1H1	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
DYNC1H1	Orphanet:209341	DYNC1H1-related autosomal dominant childhood-onset proximal spinal muscular atrophy
DYNC1H1	Orphanet:284232	Autosomal dominant Charcot-Marie-Tooth disease type 2O
EP300	Orphanet:353284	Rubinstein-Taybi syndrome due to EP300 haploinsufficiency
ITPR1	Orphanet:1065	Aniridia-cerebellar ataxia-intellectual disability syndrome
ITPR1	Orphanet:208513	Spinocerebellar ataxia type 29
ITPR1	Orphanet:98769	Spinocerebellar ataxia type 15/16
PRKCG	Orphanet:98763	Spinocerebellar ataxia type 14

Cohort genes → proteins

10 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DAGLA	HGNC:1165	ENSG00000134780	Q9Y4D2	Diacylglycerol lipase-alpha	clinvar
KIF26B	HGNC:25484	ENSG00000162849	Q2KJY2	Kinesin-like protein KIF26B	clinvar
MTCL1	HGNC:29121	ENSG00000168502	Q9Y4B5	Microtubule cross-linking factor 1	clinvar
DYNC1H1	HGNC:2961	ENSG00000197102	Q14204	Cytoplasmic dynein 1 heavy chain 1	clinvar
EP300	HGNC:3373	ENSG00000100393	Q09472	Histone acetyltransferase p300	clinvar
FAT1	HGNC:3595	ENSG00000083857	Q14517	Protocadherin Fat 1	clinvar
OPA1-AS1	HGNC:40421	ENSG00000224855		OPA1 antisense RNA 1	clinvar
BRRIAR	HGNC:59155			BHLHE40 and RIG-I regulating ITPR1 antisense RNA	clinvar
ITPR1	HGNC:6180	ENSG00000150995	Q14643	Inositol 1,4,5-trisphosphate-gated calcium channel ITPR1	clinvar
PRKCG	HGNC:9402	ENSG00000126583	P05129	Protein kinase C gamma type	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DAGLA	Diacylglycerol lipase-alpha	Serine hydrolase that hydrolyzes arachidonic acid-esterified diacylglycerols (DAGs) to produce the principal endocannabinoid, 2-arachidonoylglycerol (2-AG).
KIF26B	Kinesin-like protein KIF26B	Essential for embryonic kidney development.
MTCL1	Microtubule cross-linking factor 1	Microtubule-associated factor involved in the late phase of epithelial polarization and microtubule dynamics regulation.
DYNC1H1	Cytoplasmic dynein 1 heavy chain 1	Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules.
EP300	Histone acetyltransferase p300	Functions as a histone acetyltransferase and regulates transcription via chromatin remodeling.
FAT1	Protocadherin Fat 1	Plays an essential role for cellular polarization, directed cell migration and modulating cell-cell contact.
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).
PRKCG	Protein kinase C gamma type	Calcium-activated, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays diverse roles in neuronal cells and eye tissues, such as regulation of the neuronal receptors GRIA4/GLUR4 and GRIN1/NMDAR1, modu…

Protein-family classification

Druggable: 3 · Difficult: 1 · Unknown: 6 · Druggable fraction: 0.3

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Ion channel	1	11.2×	0.431
Kinase	1	2.8×	0.725
Enzyme (other)	1	1.2×	0.725
Other/Unknown	6	1.1×	0.725
Transcription factor	1	0.8×	0.725

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DAGLA	Enzyme (other)	yes	3.1.1.116	Fungal_lipase-type, AB_hydrolase_fold, DAG_Lipase-Related
KIF26B	Other/Unknown	no		Kinesin_motor_dom, P-loop_NTPase, Kinesin-like_fam
MTCL1	Other/Unknown	no		SOGA_CC, SOGA1/2-like_CC, MTCL1-3
DYNC1H1	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
EP300	Transcription factor	no	2.3.1.48	Znf_TAZ, Znf_ZZ, Bromodomain
FAT1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Laminin_G
OPA1-AS1	Other/Unknown	no
BRRIAR	Other/Unknown	no
ITPR1	Ion channel	yes		InsP3_rcpt, RIH_dom, Ion_trans_dom
PRKCG	Kinase	yes	2.7.11.13	C2_dom, Prot_kinase_dom, AGC-kinase_C

Expression context

Cohort genes with no expression data: 1.

7 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	9
unknown	1

Top tissues across cohort

Tissue	Cohort genes
prefrontal cortex	2
right frontal lobe	2
ganglionic eminence	2
ventricular zone	2
Brodmann (1909) area 10	1
stromal cell of endometrium	1
cerebellar cortex	1
cerebellar hemisphere	1
cerebellum	1
cortical plate	1
adrenal tissue	1
bone marrow cell	1
colonic epithelium	1
choroid plexus epithelium	1
metanephric glomerulus	1
tibia	1
bone marrow	1
calcaneal tendon	1
corpus callosum	1
Brodmann (1909) area 23	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DAGLA	171	ubiquitous	yes	right frontal lobe, prefrontal cortex, Brodmann (1909) area 10
KIF26B	113	ubiquitous	marker	ventricular zone, ganglionic eminence, stromal cell of endometrium
MTCL1	236	ubiquitous	marker	cerebellar cortex, cerebellar hemisphere, cerebellum
DYNC1H1	290	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone
EP300	292	ubiquitous	marker	colonic epithelium, adrenal tissue, bone marrow cell
FAT1	288	ubiquitous	marker	choroid plexus epithelium, tibia, metanephric glomerulus
OPA1-AS1	119		yes	calcaneal tendon, corpus callosum, bone marrow
BRRIAR
ITPR1	284	ubiquitous	marker	cauda epididymis, Brodmann (1909) area 23, primary visual cortex
PRKCG	141	broad	marker	right frontal lobe, nucleus accumbens, prefrontal cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EP300	10,122
DYNC1H1	4,215
ITPR1	3,483
FAT1	2,446
PRKCG	2,212
KIF26B	1,404
MTCL1	867
DAGLA	726
OPA1-AS1	0
BRRIAR	0

Structural data

PDB: 3 · AlphaFold-only: 5 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DYNC1H1	Q14204	97
EP300	Q09472	60
PRKCG	P05129	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DAGLA	Q9Y4D2	63.87
MTCL1	Q9Y4B5	51.33
KIF26B	Q2KJY2	45.94
FAT1	Q14517
ITPR1	Q14643

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 155. Enrichment computed across 10 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
G-protein mediated events	2	108.8×	0.006	ITPR1, PRKCG
DAG and IP3 signaling	2	105.7×	0.006	ITPR1, PRKCG
Beta-catenin independent WNT signaling	2	97.6×	0.006	ITPR1, PRKCG
Opioid Signalling	2	88.5×	0.006	ITPR1, PRKCG
PLC beta mediated events	2	88.5×	0.006	ITPR1, PRKCG
Hemostasis	3	18.0×	0.010	KIF26B, ITPR1, PRKCG
Signaling by WNT	2	37.3×	0.025	ITPR1, PRKCG
Platelet activation, signaling and aggregation	2	35.2×	0.025	ITPR1, PRKCG
Disinhibition of SNARE formation	1	380.7×	0.029	PRKCG
LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production	1	380.7×	0.029	EP300
Arachidonate production from DAG	1	380.7×	0.029	DAGLA
NFE2L2 regulating inflammation associated genes	1	380.7×	0.029	EP300
NFE2L2 regulating ER-stress associated genes	1	380.7×	0.029	EP300
Intracellular signaling by second messengers	2	30.4×	0.029	ITPR1, PRKCG
NFE2L2 regulates pentose phosphate pathway genes	1	237.9×	0.034	EP300
NFE2L2 regulating MDR associated enzymes	1	237.9×	0.034	EP300
Regulation of NFE2L2 gene expression	1	237.9×	0.034	EP300
PI5P Regulates TP53 Acetylation	1	211.5×	0.034	EP300
RUNX3 regulates p14-ARF	1	190.3×	0.034	EP300
Regulation of FOXO transcriptional activity by acetylation	1	190.3×	0.034	EP300
CLEC7A (Dectin-1) induces NFAT activation	1	173.0×	0.034	ITPR1
STAT3 nuclear events downstream of ALK signaling	1	173.0×	0.034	EP300
Regulation of gene expression by Hypoxia-inducible Factor	1	158.6×	0.034	EP300
NOTCH2 intracellular domain regulates transcription	1	158.6×	0.034	EP300
Activation of the TFAP2 (AP-2) family of transcription factors	1	158.6×	0.034	EP300
NFE2L2 regulating tumorigenic genes	1	158.6×	0.034	EP300
Nitric oxide stimulates guanylate cyclase	1	135.9×	0.034	ITPR1
RUNX3 regulates NOTCH signaling	1	135.9×	0.034	EP300
Glutamate binding, activation of AMPA receptors and synaptic plasticity	1	126.9×	0.034	PRKCG
WNT5A-dependent internalization of FZD4	1	126.9×	0.034	PRKCG

GO biological processes by enrichment

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

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of autophagy	3	90.3×	6e-04	MTCL1, EP300, ITPR1
behavioral defense response	1	2106.5×	0.007	EP300
establishment of epithelial cell apical/basal polarity involved in camera-type eye morphogenesis	1	2106.5×	0.007	FAT1
negative regulation of protein oligomerization	1	2106.5×	0.007	EP300
swimming	1	2106.5×	0.007	EP300
peptidyl-lysine propionylation	1	2106.5×	0.007	EP300
regulation of tubulin deacetylation	1	2106.5×	0.007	EP300
peptidyl-lysine crotonylation	1	2106.5×	0.007	EP300
peptidyl-lysine butyrylation	1	2106.5×	0.007	EP300
learning or memory	2	60.2×	0.007	EP300, PRKCG
internal protein amino acid acetylation	1	1053.2×	0.011	EP300
ureteric bud invasion	1	1053.2×	0.011	KIF26B
release of sequestered calcium ion into cytosol by endoplasmic reticulum	1	1053.2×	0.011	ITPR1
N-terminal peptidyl-lysine acetylation	1	702.2×	0.012	EP300
regulation of response to food	1	702.2×	0.012	PRKCG
positive regulation of mismatch repair	1	702.2×	0.012	PRKCG
retrograde trans-synaptic signaling by endocannabinoid	1	702.2×	0.012	DAGLA
cannabinoid biosynthetic process	1	702.2×	0.012	DAGLA
thigmotaxis	1	526.6×	0.014	EP300
negative regulation of chromosome condensation	1	526.6×	0.014	EP300
chemosensory behavior	1	421.3×	0.014	PRKCG
internal peptidyl-lysine acetylation	1	421.3×	0.014	EP300
regulation of metaphase plate congression	1	421.3×	0.014	DYNC1H1
response to psychosocial stress	1	421.3×	0.014	PRKCG
diacylglycerol catabolic process	1	351.1×	0.015	DAGLA
voluntary musculoskeletal movement	1	351.1×	0.015	ITPR1
establishment of spindle localization	1	351.1×	0.015	DYNC1H1
negative regulation of brown fat cell differentiation	1	351.1×	0.015	EP300
response to hypoxia	2	23.9×	0.015	EP300, ITPR1
phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway	1	263.3×	0.016	ITPR1

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 3 · Phased (≥1): 4 · Undrugged: 6

Druggability breadth: 5 of 10 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
DAGLA	ORLISTAT
PRKCG	INGENOL MEBUTATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRKCG	23	4
EP300	9	3
DAGLA	3	4
DYNC1H1	1	2
KIF26B	0	0
MTCL1	0	0
FAT1	0	0
OPA1-AS1	0	0
BRRIAR	0	0
ITPR1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ORLISTAT	4	DAGLA
INGENOL MEBUTATE	4	PRKCG
MIDOSTAURIN	4	PRKCG
TAMOXIFEN	4	PRKCG
ENTRECTINIB	4	PRKCG
COENZYME_A	3	EP300
CURCUMIN	3	EP300
EPIGALOCATECHIN GALLATE	3	EP300
SURAMIN	3	PRKCG
FASUDIL	3	PRKCG
ALVOCIDIB	3	PRKCG
ENZASTAURIN HYDROCHLORIDE	3	PRKCG
ENZASTAURIN	3	PRKCG
RUBOXISTAURIN	3	PRKCG
CANNABIDIVARIN	2	DAGLA
CANNABIDIOLIC ACID	2	DAGLA
MOLIBRESIB	2	DYNC1H1, EP300
MIVEBRESIB	2	EP300
STREPTONIGRIN	2	EP300
PHORBOL MYRISTATE ACETATE	2	PRKCG
EDELFOSINE	2	PRKCG
UPROSERTIB	2	PRKCG
UCN-01	2	PRKCG
CENISERTIB	2	PRKCG
LAUROGUADINE	2	PRKCG
LY-2090314	2	PRKCG
DAROVASERTIB	2	PRKCG
R-406	2	PRKCG
SOTRASTAURIN	2	PRKCG
BERBERINE CHLORIDE	1	EP300

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
EP300	767	Binding:763, Functional:3, ADMET:1
PRKCG	627	Binding:611, Functional:15, ADMET:1
DAGLA	48	Binding:48
ITPR1	13	Binding:12, Functional:1
DYNC1H1	7	Binding:7

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DAGLA	3.1.1.116	sn-1-specific diacylglycerol lipase
EP300	2.3.1.48	histone acetyltransferase
PRKCG	2.7.11.13	protein kinase C

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
EP300	767
PRKCG	627

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
ORLISTAT	4	DAGLA
INGENOL MEBUTATE	4	PRKCG
MIDOSTAURIN	4	PRKCG
TAMOXIFEN	4	PRKCG
ENTRECTINIB	4	PRKCG
COENZYME_A	3	EP300
CURCUMIN	3	EP300
EPIGALOCATECHIN GALLATE	3	EP300
SURAMIN	3	PRKCG
FASUDIL	3	PRKCG
ALVOCIDIB	3	PRKCG
ENZASTAURIN HYDROCHLORIDE	3	PRKCG
ENZASTAURIN	3	PRKCG
RUBOXISTAURIN	3	PRKCG
CANNABIDIVARIN	2	DAGLA
CANNABIDIOLIC ACID	2	DAGLA
MOLIBRESIB	2	DYNC1H1, EP300
MIVEBRESIB	2	EP300
STREPTONIGRIN	2	EP300
PHORBOL MYRISTATE ACETATE	2	PRKCG
EDELFOSINE	2	PRKCG
UPROSERTIB	2	PRKCG
UCN-01	2	PRKCG
CENISERTIB	2	PRKCG
LAUROGUADINE	2	PRKCG
LY-2090314	2	PRKCG
DAROVASERTIB	2	PRKCG
R-406	2	PRKCG
SOTRASTAURIN	2	PRKCG
BERBERINE CHLORIDE	1	EP300

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	DAGLA, PRKCG
B	Phased (≥1) drug, not yet approved	2	DYNC1H1, EP300
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ITPR1
E	Difficult family or no structure, no drug	5	KIF26B, MTCL1, FAT1, OPA1-AS1, BRRIAR

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KIF26B	0	—
MTCL1	0	—
FAT1	0	—
OPA1-AS1	0	—
BRRIAR	0	—
ITPR1	13	—

Clinical trials & evidence

Clinical trials

Clinical trials: 51.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	43
PHASE2	3
PHASE3	2
PHASE1	2
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03408080	PHASE3	ACTIVE_NOT_RECRUITING	Open Pilot Trial of BHV-4157
NCT03701399	PHASE3	ACTIVE_NOT_RECRUITING	Troriluzole in Adult Participants With Spinocerebellar Ataxia
NCT02960893	PHASE2/PHASE3	COMPLETED	Trial in Adult Participants With Spinocerebellar Ataxia (SCA)
NCT06397274	PHASE2	NOT_YET_RECRUITING	Stemchymal® for Polyglutamine Spinocerebellar Ataxia
NCT01350440	PHASE2	COMPLETED	Safety and Efficacy of Intravenous Immune Globulin in Treating Spinocerebellar Ataxia
NCT04301284	PHASE2	WITHDRAWN	Study of CAD-1883 for Spinocerebellar Ataxia
NCT00683943	PHASE1	COMPLETED	Lithium Treatment for Patients With Spinocerebellar Ataxia Type I
NCT02287064	PHASE1	UNKNOWN	An Open-label Trial of Intravenous Immune Globulin (IVIG)in Treating Spinocerebellar Ataxias
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02440763	Not specified	RECRUITING	The EUROSCA Natural History Study
NCT02741440	Not specified	RECRUITING	Natural History of Spinocerebellar Ataxia Type 7 (SCA7)
NCT03336008	Not specified	RECRUITING	Hong Kong Spinocerebellar Ataxias Registry
NCT04529252	Not specified	ACTIVE_NOT_RECRUITING	Investigating the Genetic and Phenotypic Presentation of Ataxia and Nucleotide Repeat Diseases
NCT05034172	Not specified	RECRUITING	Biomarker Research in Inherited Movement Disorders
NCT06034886	Not specified	AVAILABLE	Expanded Access Protocol of Troriluzole in Patients With Spinocerebellar Ataxia (SCA)
NCT06267222	Not specified	ENROLLING_BY_INVITATION	Trans-spinal Electrical Stimulation in Individuals With Spinocerebellar Ataxia
NCT06472557	Not specified	RECRUITING	Spinocerebellar Ataxia Type 27B Natural History Study (SCA27B-NHS)
NCT06529146	Not specified	ACTIVE_NOT_RECRUITING	Real-World Data Study of Troriluzole-Treated Patients With Spinocerebellar Ataxia (SCA) Compared to a Matched Natural History Control
NCT06600269	Not specified	RECRUITING	Cycling-Based Priming Coordination Training for Enhancing Ataxia Recovery and Brain Plasticity
NCT06628934	Not specified	ACTIVE_NOT_RECRUITING	Wearable Gait Sensors
NCT06633003	Not specified	RECRUITING	Effects of Oral Administration of Antrodia Cinnamomea Products for Clinical Symptoms in Spinocerebellar Ataxia Patients
NCT06898645	Not specified	NOT_YET_RECRUITING	Efficacy of Cerebellar Transcranial Magnetic Stimulation to Treat Hereditary Spinocerebellar Ataxias
NCT06904716	Not specified	ACTIVE_NOT_RECRUITING	The Study of Transcranial Magnetic Stimulation in the Regulation of Spinocerebellar Ataxia
NCT07019558	Not specified	RECRUITING	Ophthalmological Disorders in Dominant Spinal-cerebellar Ataxias
NCT07099651	Not specified	RECRUITING	Autosomal Dominant Spinocerebellar Ataxias and Social Cognition
NCT07288437	Not specified	RECRUITING	Deep Brain Stimulation for Spinocerebellar Ataxia
NCT07325487	Not specified	NOT_YET_RECRUITING	Interposed Nucleus aDBS for Ataxia
NCT00136630	Not specified	COMPLETED	Natural History, Genetic Bases and Phenotype-genotype Correlations in Autosomal Dominant Spinocerebellar Degenerations
NCT00654251	Not specified	COMPLETED	Measuring Neurological Impairment and Functional Visual Assessment In Spinocerebellar Ataxias
NCT01037777	Not specified	COMPLETED	RISCA : Prospective Study of Individuals at Risk for SCA1, SCA2, SCA3, SCA6, SCA7
NCT01975909	Not specified	COMPLETED	Transcranial Magnetic Stimulation in Spino-Cerebellar Ataxia
NCT01983631	Not specified	COMPLETED	The Effect of Whole Body Vibration Training on Neuromuscular Property in Individuals With Ataxia
NCT02103075	Not specified	COMPLETED	Neuromuscular Electrical Stimulation on Median Nerve Facilitates Low Motor Cortex Excitability in Human With Spinocerebellar Ataxia
NCT02488031	Not specified	COMPLETED	Functional and Structural Imaging and Motor Control in Spinocerebellar Ataxia
NCT02867969	Not specified	UNKNOWN	Slowing Down Disease Progression in Premanifest SCA: a Piloting Interventional Exergame Trial
NCT02874911	Not specified	COMPLETED	Coordination Training With Complete Body Video Games in Children and Adults With Degenerative Ataxias
NCT03120013	Not specified	COMPLETED	Rehabilitative Trial With Cerebello-Spinal tDCS in Neurodegenerative Ataxia
NCT03687190	Not specified	COMPLETED	Could Tai-chi Help Maintain Balance of Spinocerebellar Ataxia Patients
NCT03701776	Not specified	COMPLETED	Ataxia and Exercise Disease Using MRI and Gait Analysis
NCT03745248	Not specified	COMPLETED	Aerobic Exercise, Balance Training, and Ataxia

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
LITHIUM CARBONATE	4	1
TRORILUZOLE	3	5
ISOXAFLUTOLE	2	4
RIMTUZALCAP	2	1