Autosomal recessive spinocerebellar ataxia 14

Summary

Autosomal recessive spinocerebellar ataxia 14 (MONDO:0014159) is a disease caused by SPTBN2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SPTBN2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 74
• Phenotypes (HPO): 20

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0002073	Progressive cerebellar ataxia	Very frequent (80-99%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0001256	Intellectual disability, mild	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001272	Cerebellar atrophy	Frequent (30-79%)
HP:0001310	Dysmetria	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0001350	Slurred speech	Frequent (30-79%)
HP:0002075	Dysdiadochokinesis	Frequent (30-79%)
HP:0002078	Truncal ataxia	Frequent (30-79%)
HP:0007240	Progressive gait ataxia	Frequent (30-79%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000641	Dysmetric saccades	Occasional (5-29%)
HP:0000651	Diplopia	Occasional (5-29%)
HP:0000666	Horizontal nystagmus	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0002080	Intention tremor	Occasional (5-29%)
HP:0008003	Jerky ocular pursuit movements	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive spinocerebellar ataxia 14
Mondo ID	MONDO:0014159
OMIM	615386
Orphanet	352403
DOID	DOID:0080058
SNOMED CT	763351003
UMLS	C4706415
MedGen	1636182
GARD	0017516
Is cancer (heuristic)	no

Also known as: Ataxie spinocérébelleuse à début infantile avec retard psychomoteur · autosomal recessive cerebellar ataxia caused by mutation in SPTBN2 · autosomal recessive cerebellar ataxia-cognitive defect syndrome · autosomal recessive spinocerebellar ataxia type 14 · infantile-onset spinocerebellar ataxia-psychomotor delay syndrome · SCAR14 · SPARCA · SPARCA1 · spectrin-associated autosomal recessive cerebellar ataxia type 1 · spinocerebellar ataxia, autosomal recessive 14 · spinocerebellar ataxia, autosomal recessive type 14 · SPTBN2 autosomal recessive cerebellar ataxia

Data availability: 74 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive cerebellar ataxia › autosomal recessive spinocerebellar ataxia 14

Related subtypes (28): Charlevoix-Saguenay spastic ataxia, infantile-onset autosomal recessive nonprogressive cerebellar ataxia, autosomal recessive spinocerebellar ataxia 7, autosomal recessive ataxia, Beauce type, RIDDLE syndrome, autosomal recessive ataxia due to ubiquinone deficiency, autosomal recessive spinocerebellar ataxia 10, ataxia with oculomotor apraxia type 3, autosomal recessive spinocerebellar ataxia 16, Lichtenstein-Knorr syndrome, autosomal recessive spinocerebellar ataxia 20, spinocerebellar ataxia, autosomal recessive 22, spinocerebellar ataxia, autosomal recessive 24, autosomal recessive cerebellar ataxia - epilepsy - intellectual disability syndrome, autosomal recessive congenital cerebellar ataxia, autosomal recessive metabolic cerebellar ataxia, autosomal recessive degenerative and progressive cerebellar ataxia, autosomal recessive syndromic cerebellar ataxia, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy, spinocerebellar ataxia, autosomal recessive 29, spinocerebellar ataxia, autosomal recessive 30, spinocerebellar ataxia, autosomal recessive 31, spinocerebellar ataxia, autosomal recessive 27, spinocerebellar ataxia, autosomal recessive 28, spinocerebellar ataxia, autosomal recessive 25, spinocerebellar ataxia, autosomal recessive 26, spinocerebellar ataxia, autosomal recessive 32, spinocerebellar ataxia, autosomal recessive 33

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

74 retrieved; paginated sample, class counts are floors:

25 conflicting classifications of pathogenicity, 23 uncertain significance, 9 benign/likely benign, 6 pathogenic, 5 benign, 4 likely pathogenic, 1 likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1027424	NM_006946.4(SPTBN2):c.157+1G>A	SPTBN2	Pathogenic	criteria provided, single submitter
1048078	NM_006946.4(SPTBN2):c.1240C>T (p.Arg414Cys)	SPTBN2	Pathogenic	no assertion criteria provided
3237165	NM_006946.4(SPTBN2):c.6304G>T (p.Glu2102Ter)	SPTBN2	Pathogenic	criteria provided, single submitter
3391810	NM_006946.4(SPTBN2):c.3436C>T (p.Arg1146Ter)	SPTBN2	Pathogenic	criteria provided, single submitter
64367	NM_006946.4(SPTBN2):c.1881C>A (p.Cys627Ter)	SPTBN2	Pathogenic	no assertion criteria provided
64369	NM_006946.4(SPTBN2):c.2864_2868del (p.Thr955fs)	SPTBN2	Pathogenic	no assertion criteria provided
806696	NM_006946.4(SPTBN2):c.5991_5992del (p.Glu1997fs)	SPTBN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2412721	NM_006946.4(SPTBN2):c.2330dup (p.His777fs)	SPTBN2	Likely pathogenic	criteria provided, single submitter
2584949	NM_006946.4(SPTBN2):c.3475C>T (p.Arg1159Ter)	SPTBN2	Likely pathogenic	criteria provided, single submitter
3338468	GRCh37/hg19 11q13.2(chr11:66472691-66475714)x1	SPTBN2	Likely pathogenic	no assertion criteria provided
996593	NM_006946.4(SPTBN2):c.4444C>T (p.Arg1482Trp)	SPTBN2	Likely pathogenic	criteria provided, single submitter
1027425	NM_006946.4(SPTBN2):c.1843C>T (p.Arg615Trp)	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029116	NM_006946.4(SPTBN2):c.6802G>A (p.Val2268Met)	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1034341	NM_006946.4(SPTBN2):c.4496A>T (p.Asp1499Val)	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1256191	NM_006946.4(SPTBN2):c.7039C>T (p.Arg2347Trp)	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1400209	NM_006946.4(SPTBN2):c.2216G>A (p.Arg739His)	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1566412	NM_006946.4(SPTBN2):c.5495T>G (p.Leu1832Arg)	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1802192	NM_006946.4(SPTBN2):c.6230C>T (p.Ala2077Val)	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
195271	NM_006946.4(SPTBN2):c.157+5G>A	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2416907	NM_006946.4(SPTBN2):c.5305C>T (p.Arg1769Trp)	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2585599	NM_006946.4(SPTBN2):c.3091G>A (p.Ala1031Thr)	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2719816	NM_006946.4(SPTBN2):c.7120G>A (p.Gly2374Ser)	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305538	NM_006946.4(SPTBN2):c.6242G>A (p.Arg2081Gln)	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305541	NM_006946.4(SPTBN2):c.5950-9C>T	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305551	NM_006946.4(SPTBN2):c.4985+12G>A	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305567	NM_006946.4(SPTBN2):c.3194G>A (p.Arg1065Gln)	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305584	NM_006946.4(SPTBN2):c.1654-13G>A	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305605	NM_006946.4(SPTBN2):c.-22-10C>A	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
436855	NM_006946.4(SPTBN2):c.1653+13C>T	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
448497	NM_006946.4(SPTBN2):c.3722A>G (p.Glu1241Gly)	SPTBN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 3 · 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
SPTBN2	Definitive	Autosomal dominant	spinocerebellar ataxia type 5	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SPTBN2	Orphanet:352403	Spectrin-associated autosomal recessive cerebellar ataxia
SPTBN2	Orphanet:98766	Spinocerebellar ataxia type 5
PRKCG	Orphanet:98763	Spinocerebellar ataxia type 14

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SPTBN2	HGNC:11276	ENSG00000173898	O15020	Spectrin beta chain, non-erythrocytic 2	gencc,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)
SPTBN2	Spectrin beta chain, non-erythrocytic 2	Probably plays an important role in neuronal membrane skeleton.
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: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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
Kinase	1	13.9×	0.112
Scaffold/PPI	1	8.6×	0.112

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SPTBN2	Scaffold/PPI	no		Actinin_actin-bd_CS, PH_dom-spectrin-type, CH_dom
PRKCG	Kinase	yes	2.7.11.13	C2_dom, Prot_kinase_dom, AGC-kinase_C

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
nucleus accumbens	1
prefrontal cortex	1
right frontal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SPTBN2	238	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
PRKCG	141	broad	marker	right frontal lobe, nucleus accumbens, prefrontal cortex

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRKCG	2,212
SPTBN2	1,735

Intra-cohort edges

A	B	Sources
PRKCG	SPTBN2	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SPTBN2	O15020	3
PRKCG	P05129	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 47. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

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

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Disinhibition of SNARE formation	1	1142.0×	0.022	PRKCG
Glutamate binding, activation of AMPA receptors and synaptic plasticity	1	380.7×	0.022	PRKCG
WNT5A-dependent internalization of FZD4	1	380.7×	0.022	PRKCG
Trafficking of GluR2-containing AMPA receptors	1	335.9×	0.022	PRKCG
Trafficking of AMPA receptors	1	271.9×	0.022	PRKCG
Calmodulin induced events	1	190.3×	0.022	PRKCG
CaM pathway	1	190.3×	0.022	PRKCG
Ca-dependent events	1	184.2×	0.022	PRKCG
Interaction between L1 and Ankyrins	1	184.2×	0.022	SPTBN2
G-protein mediated events	1	163.1×	0.022	PRKCG
DAG and IP3 signaling	1	158.6×	0.022	PRKCG
PCP/CE pathway	1	150.3×	0.022	PRKCG
Beta-catenin independent WNT signaling	1	146.4×	0.022	PRKCG
NCAM signaling for neurite out-growth	1	135.9×	0.022	SPTBN2
Opioid Signalling	1	132.8×	0.022	PRKCG
PLC beta mediated events	1	132.8×	0.022	PRKCG
G alpha (z) signalling events	1	116.5×	0.024	PRKCG
Signal Transduction	2	10.2×	0.025	SPTBN2, PRKCG
Response to elevated platelet cytosolic Ca2+	1	81.6×	0.030	PRKCG
ER to Golgi Anterograde Transport	1	66.4×	0.033	SPTBN2
MAPK1/MAPK3 signaling	1	65.6×	0.033	SPTBN2
L1CAM interactions	1	60.1×	0.033	SPTBN2
Signaling by WNT	1	56.0×	0.033	PRKCG
COPI-mediated anterograde transport	1	54.9×	0.033	SPTBN2
Platelet activation, signaling and aggregation	1	52.9×	0.033	PRKCG
MAPK family signaling cascades	1	51.4×	0.033	SPTBN2
Transport to the Golgi and subsequent modification	1	51.4×	0.033	SPTBN2
Neurotransmitter receptors and postsynaptic signal transmission	1	50.1×	0.033	PRKCG
Intracellular signaling by second messengers	1	45.7×	0.035	PRKCG
MHC class II antigen presentation	1	44.6×	0.035	SPTBN2

GO biological processes by enrichment

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

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cerebellar Purkinje cell layer morphogenesis	1	4213.0×	0.003	SPTBN2
regulation of response to food	1	2808.7×	0.003	PRKCG
positive regulation of mismatch repair	1	2808.7×	0.003	PRKCG
regulation of postsynaptic specialization assembly	1	2106.5×	0.003	SPTBN2
chemosensory behavior	1	1685.2×	0.003	PRKCG
response to psychosocial stress	1	1685.2×	0.003	PRKCG
response to angiotensin	1	936.2×	0.004	PRKCG
regulation of phagocytosis	1	842.6×	0.004	PRKCG
actin filament capping	1	766.0×	0.004	SPTBN2
synaptic signaling via neuropeptide	1	766.0×	0.004	PRKCG
negative regulation of proteasomal protein catabolic process	1	702.2×	0.004	PRKCG
response to morphine	1	601.9×	0.004	PRKCG
response to pain	1	443.5×	0.005	PRKCG
innervation	1	443.5×	0.005	PRKCG
adult behavior	1	234.1×	0.008	SPTBN2
presynaptic modulation of chemical synaptic transmission	1	227.7×	0.008	PRKCG
regulation of synaptic vesicle exocytosis	1	227.7×	0.008	PRKCG
negative regulation of protein catabolic process	1	183.2×	0.010	PRKCG
negative regulation of protein ubiquitination	1	142.8×	0.011	PRKCG
long-term synaptic potentiation	1	140.4×	0.011	PRKCG
regulation of circadian rhythm	1	129.6×	0.012	PRKCG
rhythmic process	1	125.8×	0.012	PRKCG
learning or memory	1	120.4×	0.012	PRKCG
synapse assembly	1	115.4×	0.012	SPTBN2
response to toxic substance	1	105.3×	0.012	PRKCG
multicellular organism growth	1	68.5×	0.018	SPTBN2
phospholipase C-activating G protein-coupled receptor signaling pathway	1	65.8×	0.018	PRKCG
negative regulation of neuron apoptotic process	1	55.4×	0.021	PRKCG
vesicle-mediated transport	1	48.1×	0.023	SPTBN2
actin cytoskeleton organization	1	39.6×	0.027	SPTBN2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 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
PRKCG	INGENOL MEBUTATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRKCG	23	4
SPTBN2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
INGENOL MEBUTATE	4	PRKCG
MIDOSTAURIN	4	PRKCG
TAMOXIFEN	4	PRKCG
ENTRECTINIB	4	PRKCG
SURAMIN	3	PRKCG
FASUDIL	3	PRKCG
ALVOCIDIB	3	PRKCG
ENZASTAURIN HYDROCHLORIDE	3	PRKCG
ENZASTAURIN	3	PRKCG
RUBOXISTAURIN	3	PRKCG
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
PF-00562271	1	PRKCG
RG-1530	1	PRKCG
PF-03758309	1	PRKCG

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PRKCG	627	Binding:611, Functional:15, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
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
PRKCG	627

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

23 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)
INGENOL MEBUTATE	4	PRKCG
MIDOSTAURIN	4	PRKCG
TAMOXIFEN	4	PRKCG
ENTRECTINIB	4	PRKCG
SURAMIN	3	PRKCG
FASUDIL	3	PRKCG
ALVOCIDIB	3	PRKCG
ENZASTAURIN HYDROCHLORIDE	3	PRKCG
ENZASTAURIN	3	PRKCG
RUBOXISTAURIN	3	PRKCG
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
PF-00562271	1	PRKCG
RG-1530	1	PRKCG
PF-03758309	1	PRKCG

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PRKCG
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SPTBN2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SPTBN2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.