Autosomal recessive cerebellar ataxia-saccadic intrusion syndrome

Summary

Autosomal recessive cerebellar ataxia-saccadic intrusion syndrome (MONDO:0011811) is a disease caused by VPS13D (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: VPS13D (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 92
• Phenotypes (HPO): 20

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		27	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:0002066	Gait ataxia	Very frequent (80-99%)
HP:0002070	Limb ataxia	Very frequent (80-99%)
HP:0002073	Progressive cerebellar ataxia	Very frequent (80-99%)
HP:0002078	Truncal ataxia	Very frequent (80-99%)
HP:0002366	Abnormal lower motor neuron morphology	Very frequent (80-99%)
HP:0002493	Upper motor neuron dysfunction	Very frequent (80-99%)
HP:0003474	Somatic sensory dysfunction	Very frequent (80-99%)
HP:0007256	Abnormal pyramidal sign	Very frequent (80-99%)
HP:0025404	Abnormal visual fixation	Very frequent (80-99%)
HP:0000496	Abnormality of eye movement	Frequent (30-79%)
HP:0000570	Abnormal saccadic eye movements	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0002317	Unsteady gait	Frequent (30-79%)
HP:0002380	Fasciculations	Frequent (30-79%)
HP:0007141	Sensorimotor neuropathy	Frequent (30-79%)
HP:0007338	Hypermetric saccades	Frequent (30-79%)
HP:0010522	Dyslexia	Frequent (30-79%)
HP:0010831	Impaired proprioception	Frequent (30-79%)
HP:0001336	Myoclonus	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive cerebellar ataxia-saccadic intrusion syndrome
Mondo ID	MONDO:0011811
MeSH	C537310
OMIM	607317
Orphanet	95434
DOID	DOID:0111611
UMLS	C1846492
MedGen	335442
GARD	0004952
Is cancer (heuristic)	no

Also known as: SCAR4 · SCASI · spinocerebellar ataxia 24 · spinocerebellar ataxia 24 (formerly) · spinocerebellar ataxia autosomal recessive 4 · spinocerebellar ataxia, autosomal recessive 4

Data availability: 92 ClinVar variants · 6 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 syndromic cerebellar ataxia › autosomal recessive cerebellar ataxia-saccadic intrusion syndrome

Related subtypes (6): autosomal recessive spinocerebellar ataxia 11, peroxisome biogenesis disorder 4B, ataxia - oculomotor apraxia type 4, acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome, Gemignani syndrome, cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome

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

92 retrieved; paginated sample, class counts are floors:

51 uncertain significance, 18 likely pathogenic, 10 pathogenic, 6 conflicting classifications of pathogenicity, 4 pathogenic/likely pathogenic, 2 benign/likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1064611	NM_015378.4(VPS13D):c.941+3A>G	VPS13D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456771	NM_015378.4(VPS13D):c.9757C>T (p.Arg3253Ter)	VPS13D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1703244	NM_015378.4(VPS13D):c.11926del (p.Gln3976fs)	VPS13D	Pathogenic	criteria provided, single submitter
2444418	NM_015378.4(VPS13D):c.9871+2T>C	VPS13D	Pathogenic	criteria provided, single submitter
2664706	NM_015378.4(VPS13D):c.5725+2dup	VPS13D	Pathogenic	criteria provided, single submitter
3255090	NM_015378.4(VPS13D):c.1055dup (p.Tyr352Ter)	VPS13D	Pathogenic	criteria provided, single submitter
561198	NM_015378.4(VPS13D):c.3569G>A (p.Gly1190Asp)	VPS13D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
561199	NM_015378.4(VPS13D):c.3316C>T (p.Gln1106Ter)	VPS13D	Pathogenic	criteria provided, single submitter
561200	NM_015378.4(VPS13D):c.12629C>T (p.Ala4210Val)	VPS13D	Pathogenic	criteria provided, single submitter
561201	NM_015378.4(VPS13D):c.5409C>A (p.Tyr1803Ter)	VPS13D	Pathogenic	no assertion criteria provided
561202	NM_015378.4(VPS13D):c.7334_7335del (p.Val2445fs)	VPS13D	Pathogenic	no assertion criteria provided
807523	NM_015378.4(VPS13D):c.2020C>T (p.Arg674Ter)	VPS13D	Pathogenic	criteria provided, single submitter
933227	NM_015378.4(VPS13D):c.946C>T (p.Arg316Ter)	VPS13D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
983262	NM_015378.4(VPS13D):c.12350C>G (p.Ser4117Ter)	VPS13D	Pathogenic	criteria provided, single submitter
1029390	NM_015378.4(VPS13D):c.1183C>T (p.Arg395Ter)	VPS13D	Likely pathogenic	criteria provided, single submitter
1064612	NM_015378.4(VPS13D):c.10270C>T (p.Gln3424Ter)	VPS13D	Likely pathogenic	criteria provided, single submitter
1687497	NM_015378.4(VPS13D):c.8983C>T (p.Arg2995Ter)	VPS13D	Likely pathogenic	criteria provided, single submitter
1703245	NM_015378.4(VPS13D):c.12242T>C (p.Val4081Ala)	VPS13D	Likely pathogenic	criteria provided, single submitter
2434589	NM_015378.4(VPS13D):c.5087dup (p.Pro1697fs)	VPS13D	Likely pathogenic	criteria provided, single submitter
3765500	NM_015378.4(VPS13D):c.1308G>A (p.Trp436Ter)	VPS13D	Likely pathogenic	no assertion criteria provided
3765505	NM_015378.4(VPS13D):c.12395G>A (p.Arg4132Gln)	VPS13D	Likely pathogenic	no assertion criteria provided
3767166	NM_015378.4(VPS13D):c.6628C>T (p.Gln2210Ter)	VPS13D	Likely pathogenic	criteria provided, single submitter
4293136	NM_015378.4(VPS13D):c.12408_12409dup (p.Tyr4137fs)	VPS13D	Likely pathogenic	criteria provided, single submitter
4536616	NM_015378.4(VPS13D):c.12794+1G>T	VPS13D	Likely pathogenic	criteria provided, single submitter
4536617	NM_015378.4(VPS13D):c.9301C>T (p.Arg3101Trp)	VPS13D	Likely pathogenic	criteria provided, single submitter
4687235	NM_015378.4(VPS13D):c.1212+1G>C	VPS13D	Likely pathogenic	criteria provided, single submitter
4813053	NM_015378.4(VPS13D):c.3943C>T (p.Arg1315Ter)	VPS13D	Likely pathogenic	criteria provided, single submitter
4813070	NM_015378.4(VPS13D):c.12424del (p.Ser4142fs)	VPS13D	Likely pathogenic	criteria provided, single submitter
561203	NM_015378.4(VPS13D):c.10562A>G (p.Asn3521Ser)	VPS13D	Likely pathogenic	criteria provided, single submitter
807716	NM_015378.4(VPS13D):c.12743C>A (p.Ala4248Glu)	VPS13D	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 2 · 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
VPS13D	Strong	Autosomal recessive	autosomal recessive cerebellar ataxia-saccadic intrusion syndrome	5
VPS41	Strong	Autosomal recessive	spinocerebellar ataxia, autosomal recessive 29	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VPS13D	Orphanet:95434	Autosomal recessive cerebellar ataxia-movement disorder syndrome
VPS41	Orphanet:95434	Autosomal recessive cerebellar ataxia-movement disorder syndrome

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
VPS13D	HGNC:23595	ENSG00000048707	Q5THJ4	Intermembrane lipid transfer protein VPS13D	gencc,clinvar
VPS41	HGNC:12713	ENSG00000006715	P49754	Vacuolar protein sorting-associated protein 41 homolog	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VPS13D	Intermembrane lipid transfer protein VPS13D	Mediates the transfer of lipids between membranes at organelle contact sites.
VPS41	Vacuolar protein sorting-associated protein 41 homolog	Plays a role in vesicle-mediated protein trafficking to lysosomal compartments including the endocytic membrane transport and autophagic pathways.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.0

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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VPS13D	Other/Unknown	no		UBA-like_sf, VPS13_VAB, UBA
VPS41	Transcription factor	no		Clathrin_H-chain/VPS_repeat, Znf_RING, TPR-like_helical_dom_sf

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
skin of abdomen	1
skin of leg	1
sural nerve	1
adrenal tissue	1
calcaneal tendon	1
gall bladder	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VPS13D	299	ubiquitous	marker	skin of leg, skin of abdomen, sural nerve
VPS41	275	ubiquitous	marker	calcaneal tendon, adrenal tissue, gall bladder

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VPS13D	1,171
VPS41	1,068

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
VPS41	P49754	86.63
VPS13D	Q5THJ4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
SARS-CoV-2 modulates autophagy	1	1038.2×	1e-03	VPS41

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
protein targeting to vacuole	2	1296.3×	7e-06	VPS13D, VPS41
protein retention in Golgi apparatus	1	1685.2×	0.004	VPS13D
Golgi vesicle transport	1	766.0×	0.004	VPS41
regulation of SNARE complex assembly	1	648.1×	0.004	VPS41
endosomal vesicle fusion	1	561.7×	0.004	VPS41
positive regulation of mitophagy	1	561.7×	0.004	VPS13D
late endosome to lysosome transport	1	495.6×	0.004	VPS41
endosome to lysosome transport	1	168.5×	0.010	VPS41
lipid transport	1	131.7×	0.011	VPS13D
macroautophagy	1	120.4×	0.011	VPS41
cellular response to starvation	1	96.8×	0.012	VPS41
mitochondrion organization	1	75.9×	0.014	VPS13D
vesicle-mediated transport	1	48.1×	0.021	VPS41

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
VPS13D	0	0
VPS41	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	VPS13D, VPS41

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
VPS13D	0	—
VPS41	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.