Spinocerebellar ataxia 46

Summary

Spinocerebellar ataxia 46 (MONDO:0033481) is a disease with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 10

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

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

Identifiers

Disease identifiers

Field	Value
Canonical name	spinocerebellar ataxia 46
Mondo ID	MONDO:0033481
OMIM	617770
Orphanet	589522
DOID	DOID:0080288
UMLS	C4540404
MedGen	1624251
GARD	0022352
Is cancer (heuristic)	no

Also known as: SCA46 · spinocerebellar ataxia 46

Data availability: 10 ClinVar variants · 3 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 dominant disease › autosomal dominant cerebellar ataxia › autosomal dominant cerebellar ataxia type I › spinocerebellar ataxia 46

Related subtypes (29): Machado-Joseph disease, spinocerebellar ataxia type 29, spinocerebellar ataxia type 34, spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia type 4, cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome, autosomal dominant cerebellar ataxia, deafness and narcolepsy, spinocerebellar ataxia type 12, spinocerebellar ataxia type 13, spinocerebellar ataxia type 14, spinocerebellar ataxia type 15/16, spinocerebellar ataxia type 17, spinocerebellar ataxia type 19/22, spinocerebellar ataxia type 21, spinocerebellar ataxia type 18, spinocerebellar ataxia type 20, spinocerebellar ataxia type 25, spinocerebellar ataxia type 8, spinocerebellar ataxia type 27, spinocerebellar ataxia type 23, spinocerebellar ataxia type 28, spinocerebellar ataxia type 35, spinocerebellar ataxia type 32, spinocerebellar ataxia type 36, cerebellar dysfunction with variable cognitive and behavioral abnormalities, spinocerebellar ataxia type 37, spinocerebellar ataxia type 40, neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism

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

10 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 1 benign, 1 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
637402	NM_181882.3(PRX):c.3198del (p.Phe1066fs)	PLD3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
803558	NC_000019.10:g.40394766del	PLD3	Pathogenic	criteria provided, single submitter
1705294	NM_012268.4(PLD3):c.602A>T (p.His201Leu)	PLD3	Uncertain significance	criteria provided, single submitter
2279805	NM_012268.4(PLD3):c.1123C>T (p.Arg375Trp)	PLD3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2464305	NM_012268.4(PLD3):c.1195G>A (p.Val399Met)	PLD3	Uncertain significance	criteria provided, multiple submitters, no conflicts
3892106	NM_012268.4(PLD3):c.937A>G (p.Asn313Asp)	PLD3	Uncertain significance	criteria provided, multiple submitters, no conflicts
4086140	NM_012268.4(PLD3):c.730C>G (p.Leu244Val)	PLD3	Uncertain significance	criteria provided, single submitter
446268	NM_012268.4(PLD3):c.923T>C (p.Leu308Pro)	PLD3	Uncertain significance	criteria provided, single submitter
983041	NM_012268.4(PLD3):c.615G>A (p.Trp205Ter)	PLD3	Uncertain significance	criteria provided, single submitter
215547	NM_181882.3(PRX):c.4059GGA[6] (p.Glu1361del)	PRX	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
PLD3	Moderate	Autosomal dominant	spinocerebellar ataxia 46	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PLD3	Orphanet:589522	Spinocerebellar ataxia type 46
PRX	Orphanet:64748	Dejerine-Sottas syndrome
PRX	Orphanet:99952	Charcot-Marie-Tooth disease type 4F

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PLD3	HGNC:17158	ENSG00000105223	Q8IV08	5’-3’ exonuclease PLD3	gencc,clinvar
PRX	HGNC:13797	ENSG00000105227	Q9BXM0	Periaxin	clinvar
PRDX6	HGNC:16753	ENSG00000117592	P30041	Peroxiredoxin-6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PLD3	5’-3’ exonuclease PLD3	5’->3’ exonuclease that hydrolyzes the phosphodiester bond of single-stranded DNA (ssDNA) and RNA molecules to form nucleoside 3’-monophosphates and 5’-end 5’-hydroxy deoxyribonucleotide/ribonucleotide fragments.
PRX	Periaxin	Scaffolding protein that functions as part of a dystroglycan complex in Schwann cells, and as part of EZR and AHNAK-containing complexes in eye lens fiber cells.
PRDX6	Peroxiredoxin-6	Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

Family distribution

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

Family	Genes	Fold	FDR
Scaffold/PPI	1	5.8×	0.345
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PLD3	Other/Unknown	no		PLipase_D/transphosphatidylase, PLDc_3, Diverse_PLD-related
PRX	Scaffold/PPI	no		PDZ, PDZ_sf, Myelin_sheath_structural
PRDX6	Enzyme (other)	yes	1.11.1.27	AhpC/TSA, Thioredoxin_domain, Peroxiredoxin_C

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adenohypophysis	1
pituitary gland	1
right frontal lobe	1
olfactory bulb	1
sural nerve	1
trigeminal ganglion	1
corpus epididymis	1
gastrocnemius	1
mucosa of stomach	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PLD3	282	ubiquitous	marker	adenohypophysis, pituitary gland, right frontal lobe
PRX	258	ubiquitous	marker	olfactory bulb, trigeminal ganglion, sural nerve
PRDX6	295	ubiquitous	marker	corpus epididymis, gastrocnemius, mucosa of stomach

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRDX6	4,106
PRX	1,569
PLD3	1,540

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PLD3	Q8IV08	7
PRDX6	P30041	3
PRX	Q9BXM0	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Synthesis of PG	1	423.0×	0.012	PLD3
Role of phospholipids in phagocytosis	1	152.3×	0.012	PLD3
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	122.8×	0.012	PRX
Detoxification of Reactive Oxygen Species	1	100.2×	0.012	PRDX6
Neutrophil degranulation	1	7.7×	0.124	PRDX6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
axon ensheathment	1	936.2×	0.005	PRX
myotube differentiation	1	702.2×	0.005	PLD3
cellular oxidant detoxification	1	624.1×	0.005	PRDX6
regulation of cytokine production involved in inflammatory response	1	624.1×	0.005	PLD3
peripheral nervous system myelin maintenance	1	510.7×	0.005	PRX
glycerophospholipid catabolic process	1	351.1×	0.007	PRDX6
hydrogen peroxide catabolic process	1	224.7×	0.009	PRDX6
positive regulation of mRNA splicing, via spliceosome	1	181.2×	0.010	PRDX6
immune system process	1	130.6×	0.012	PLD3
cell redox homeostasis	1	114.6×	0.012	PRDX6
regulation of RNA splicing	1	73.0×	0.017	PRX
response to oxidative stress	1	43.5×	0.027	PRDX6
lipid metabolic process	1	30.5×	0.035	PLD3
inflammatory response	1	12.6×	0.077	PLD3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PLD3	0	0
PRX	0	0
PRDX6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PRDX6	15	Binding:15
PLD3	13	Binding:13

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PRDX6	1.11.1.27, 2.3.1.23, 3.1.1.4	glutathione-dependent peroxiredoxin, 1-acylglycerophosphocholine O-acyltransferase, phospholipase A2

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	PRDX6
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	PLD3, PRX

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PLD3	13	—
PRX	0	—
PRDX6	15	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.