Spinocerebellar ataxia 45

Summary

Spinocerebellar ataxia 45 (MONDO:0033480) is a disease caused by FAT2 (GenCC Strong), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FAT2 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 61

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	spinocerebellar ataxia 45
Mondo ID	MONDO:0033480
OMIM	617769
Orphanet	589527
DOID	DOID:0080287
UMLS	C4540400
MedGen	1622156
GARD	0022353
Is cancer (heuristic)	no

Also known as: SCA45 · spinocerebellar ataxia 45

Data availability: 61 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 dominant disease › autosomal dominant cerebellar ataxia › autosomal dominant cerebellar ataxia type III › spinocerebellar ataxia 45

Related subtypes (9): spinocerebellar ataxia type 31, spinocerebellar ataxia type 6, spinocerebellar ataxia type 5, spinocerebellar ataxia type 11, spinocerebellar ataxia type 26, spinocerebellar ataxia type 30, spinocerebellar ataxia type 38, spinocerebellar ataxia type 41, spinocerebellar ataxia type 42

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

61 retrieved; paginated sample, class counts are floors:

24 benign, 24 uncertain significance, 5 conflicting classifications of pathogenicity, 4 likely benign, 2 benign/likely benign, 1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
16236	NM_000143.4(FH):c.698G>A (p.Arg233His)	FH	Pathogenic	criteria provided, multiple submitters, no conflicts
3064881	NM_001447.3(FAT2):c.3632A>C (p.Glu1211Ala)	FAT2	Likely pathogenic	criteria provided, single submitter
2580963	NM_004360.5(CDH1):c.1062del (p.Gly354_Leu355insTer)	CDH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2047312	NM_001447.3(FAT2):c.269G>A (p.Gly90Asp)	FAT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2441365	NM_001447.3(FAT2):c.10111A>G (p.Ile3371Val)	FAT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
708910	NM_001447.3(FAT2):c.3976C>T (p.Leu1326Phe)	FAT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2767624	NM_001447.3(FAT2):c.9805C>T (p.Arg3269Cys)	SLC36A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1180502	NM_001447.3(FAT2):c.9896C>T (p.Ser3299Phe)	FAT2	Uncertain significance	criteria provided, single submitter
1298317	NM_001447.3(FAT2):c.12899T>C (p.Met4300Thr)	FAT2	Uncertain significance	no assertion criteria provided
1301622	NM_001447.3(FAT2):c.1521T>G (p.Ile507Met)	FAT2	Uncertain significance	criteria provided, single submitter
1333870	NM_001447.3(FAT2):c.5237T>C (p.Val1746Ala)	FAT2	Uncertain significance	criteria provided, single submitter
1679143	NM_001447.3(FAT2):c.9835C>G (p.Leu3279Val)	FAT2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1708205	NM_001447.3(FAT2):c.1653del (p.Leu552fs)	FAT2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2200741	NM_001447.3(FAT2):c.7757A>G (p.Lys2586Arg)	FAT2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2411727	NM_001447.3(FAT2):c.5449C>T (p.Pro1817Ser)	FAT2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2421867	NM_001447.3(FAT2):c.11792C>T (p.Thr3931Met)	FAT2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2441362	NM_001447.3(FAT2):c.11435C>T (p.Thr3812Ile)	FAT2	Uncertain significance	criteria provided, single submitter
2441363	NM_001447.3(FAT2):c.3781G>C (p.Gly1261Arg)	FAT2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2441364	NM_001447.3(FAT2):c.12337A>G (p.Asn4113Asp)	FAT2	Uncertain significance	criteria provided, single submitter
3068044	NM_001447.3(FAT2):c.7018G>A (p.Glu2340Lys)	FAT2	Uncertain significance	criteria provided, single submitter
3238748	NM_001447.3(FAT2):c.5662G>A (p.Gly1888Ser)	FAT2	Uncertain significance	criteria provided, single submitter
3254986	NM_001447.3(FAT2):c.436C>T (p.Pro146Ser)	FAT2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3377682	NM_001447.3(FAT2):c.7652G>A (p.Arg2551Lys)	FAT2	Uncertain significance	criteria provided, single submitter
3848981	NM_001447.3(FAT2):c.3236C>A (p.Ala1079Asp)	FAT2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3891846	NM_001447.3(FAT2):c.5163G>T (p.Glu1721Asp)	FAT2	Uncertain significance	criteria provided, single submitter
3891849	NM_001447.3(FAT2):c.5347A>C (p.Asn1783His)	FAT2	Uncertain significance	criteria provided, single submitter
3891852	NM_001447.3(FAT2):c.6742A>G (p.Thr2248Ala)	FAT2	Uncertain significance	criteria provided, single submitter
446265	NM_001447.3(FAT2):c.10758G>C (p.Lys3586Asn)	FAT2	Uncertain significance	criteria provided, single submitter
446266	NM_001447.3(FAT2):c.10946G>A (p.Arg3649Gln)	FAT2	Uncertain significance	criteria provided, single submitter
973877	NM_001447.3(FAT2):c.11978C>T (p.Ala3993Val)	FAT2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 9 · 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
FAT2	Strong	Autosomal dominant	spinocerebellar ataxia 45	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FAT2	Orphanet:589527	Spinocerebellar ataxia type 45
CDH1	Orphanet:1331	Familial prostate cancer
CDH1	Orphanet:199306	Cleft lip/palate
CDH1	Orphanet:1997	Blepharo-cheilo-odontic syndrome
CDH1	Orphanet:227535	Hereditary breast cancer
CDH1	Orphanet:26106	Hereditary diffuse gastric cancer
FH	Orphanet:24	Fumaric aciduria
FH	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
FH	Orphanet:523	Hereditary leiomyomatosis and renal cell cancer

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FAT2	HGNC:3596	ENSG00000086570	Q9NYQ8	Protocadherin Fat 2	gencc,clinvar
CDH1	HGNC:1748	ENSG00000039068	P12830	Cadherin-1	clinvar
SLC36A1	HGNC:18761	ENSG00000123643	Q7Z2H8	Proton-coupled amino acid transporter 1	clinvar
FH	HGNC:3700	ENSG00000091483	P07954	Fumarate hydratase, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FAT2	Protocadherin Fat 2	Involved in the regulation of cell migration.
CDH1	Cadherin-1	Cadherins are calcium-dependent cell adhesion proteins.
SLC36A1	Proton-coupled amino acid transporter 1	Electrogenic proton/amino acid symporter with selectivity for small apolar L-amino acids, their D-enantiomers and selected amino acid derivatives such as 4-aminobutanoate/GABA.
FH	Fumarate hydratase, mitochondrial	Catalyzes the reversible stereospecific interconversion of fumarate to L-malate.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25

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
Enzyme (other)	1	3.0×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FAT2	Other/Unknown	no		EGF, Laminin_G, EGF-like_Ca-bd_dom
CDH1	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Cadherin_pro_dom
SLC36A1	Other/Unknown	no		AA_transpt_TM
FH	Enzyme (other)	yes	4.2.1.2	Fumarate_lyase_fam, Fum_hydII, L-Aspartase-like

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
jejunal mucosa	2
cerebellar cortex	1
cerebellar vermis	1
paraflocculus	1
esophagus squamous epithelium	1
gingival epithelium	1
duodenum	1
right hemisphere of cerebellum	1
body of tongue	1
cardiac ventricle	1
heart right ventricle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FAT2	182	broad	marker	paraflocculus, cerebellar vermis, cerebellar cortex
CDH1	245	broad	marker	jejunal mucosa, esophagus squamous epithelium, gingival epithelium
SLC36A1	247	ubiquitous	marker	jejunal mucosa, duodenum, right hemisphere of cerebellum
FH	292	ubiquitous	marker	heart right ventricle, body of tongue, cardiac ventricle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CDH1	8,738
FH	3,709
FAT2	1,223
SLC36A1	1,218

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CDH1	P12830	22
FH	P07954	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC36A1	Q7Z2H8	84.95
FAT2	Q9NYQ8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 51. Enrichment computed across 4 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
Proton-coupled neutral amino acid transporters	1	1903.3×	0.019	SLC36A1
Epithelial-Mesenchymal Transition (EMT) during gastrulation	1	475.8×	0.019	CDH1
InlA-mediated entry of Listeria monocytogenes into host cells	1	423.0×	0.019	CDH1
Apoptotic cleavage of cell adhesion proteins	1	346.1×	0.019	CDH1
Listeria monocytogenes entry into host cells	1	346.1×	0.019	CDH1
Regulation of CDH1 mRNA translation by microRNAs	1	346.1×	0.019	CDH1
Regulation of CDH1 Function	1	317.2×	0.019	CDH1
Positive Regulation of CDH1 Gene Transcription	1	317.2×	0.019	CDH1
Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition	1	292.8×	0.019	CDH1
Developmental Lineage of Mammary Stem Cells	1	253.8×	0.019	CDH1
Formation of definitive endoderm	1	237.9×	0.019	CDH1
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	181.3×	0.021	CDH1
SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)	1	165.5×	0.021	CDH1
Apoptotic cleavage of cellular proteins	1	158.6×	0.021	CDH1
Apoptotic execution phase	1	158.6×	0.021	CDH1
Developmental Lineage of Mammary Gland Luminal Epithelial Cells	1	152.3×	0.021	CDH1
Citric acid cycle (TCA cycle)	1	141.0×	0.021	FH
RHO GTPases activate IQGAPs	1	115.3×	0.023	CDH1
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	1	112.0×	0.023	CDH1
Bacterial Infection Pathways	1	112.0×	0.023	CDH1
Amino acid transport across the plasma membrane	1	100.2×	0.024	SLC36A1
Gastrulation	1	86.5×	0.026	CDH1
Adherens junctions interactions	1	82.8×	0.026	CDH1
Cell-cell junction organization	1	82.8×	0.026	CDH1
Degradation of CDH1	1	65.6×	0.030	CDH1
Cell junction organization	1	62.4×	0.030	CDH1
MITF-M-dependent gene expression	1	60.4×	0.030	CDH1
Transcriptional and post-translational regulation of MITF-M expression and activity	1	59.5×	0.030	CDH1
Apoptosis	1	56.0×	0.031	CDH1
Activation of STAT3 by cadherin engagement	1	54.4×	0.031	CDH1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cell-cell adhesion mediated by cadherin	2	205.5×	0.002	FAT2, CDH1
fumarate metabolic process	1	4213.0×	0.005	FH
homophilic cell-cell adhesion	2	70.2×	0.005	FAT2, CDH1
obsolete regulation of arginine metabolic process	1	2106.5×	0.006	FH
response to heparin	1	1404.3×	0.006	CDH1
regulation of protein catabolic process at postsynapse, modulating synaptic transmission	1	1053.2×	0.006	CDH1
proline transmembrane transport	1	842.6×	0.006	SLC36A1
cellular response to indole-3-methanol	1	842.6×	0.006	CDH1
taurine transmembrane transport	1	702.2×	0.006	SLC36A1
response to Gram-positive bacterium	1	702.2×	0.006	CDH1
desmosome assembly	1	601.9×	0.006	CDH1
arginine metabolic process	1	601.9×	0.006	FH
L-alanine transport	1	601.9×	0.006	SLC36A1
alanine transport	1	601.9×	0.006	SLC36A1
malate metabolic process	1	468.1×	0.007	FH
glycine transport	1	351.1×	0.008	SLC36A1
positive regulation of protein localization	1	351.1×	0.008	CDH1
urea cycle	1	324.1×	0.008	FH
proline transport	1	324.1×	0.008	SLC36A1
cellular response to lithium ion	1	280.9×	0.009	CDH1
amino acid import across plasma membrane	1	263.3×	0.009	SLC36A1
negative regulation of cell-cell adhesion	1	247.8×	0.009	CDH1
positive regulation of double-strand break repair via nonhomologous end joining	1	247.8×	0.009	FH
epithelial cell migration	1	234.1×	0.009	FAT2
cell-substrate adhesion	1	191.5×	0.010	FAT2
negative regulation of axon extension	1	183.2×	0.010	CDH1
pituitary gland development	1	162.0×	0.011	CDH1
tricarboxylic acid cycle	1	127.7×	0.013	FH
adherens junction organization	1	127.7×	0.013	CDH1
calcium-dependent cell-cell adhesion	1	120.4×	0.014	CDH1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FAT2	0	0
CDH1	0	0
SLC36A1	0	0
FH	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
CDH1	18	Binding:18
SLC36A1	3	Binding:3
FH	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FH	4.2.1.2	fumarate hydratase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	FH
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	FAT2, CDH1, SLC36A1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FAT2	0	—
CDH1	18	—
SLC36A1	3	—
FH	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.