Spinocerebellar ataxia, autosomal recessive 29

Summary

Spinocerebellar ataxia, autosomal recessive 29 (MONDO:0030312) is a disease caused by VPS41 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: VPS41 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 18

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	spinocerebellar ataxia, autosomal recessive 29
Mondo ID	MONDO:0030312
OMIM	619389
DOID	DOID:0070410
UMLS	C5543595
MedGen	1788435
GARD	0025534
Is cancer (heuristic)	no

Also known as: Barakat-Van Ham-Kaya syndrome · neurodevelopmental disorder with hypotonia and cerebellar ataxia · SCAR29 · spinocerebellar ataxia, autosomal recessive 29

Data availability: 18 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 recessive disease › autosomal recessive cerebellar ataxia › spinocerebellar ataxia, autosomal recessive 29

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 14, 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 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

18 retrieved; paginated sample, class counts are floors:

7 likely pathogenic, 7 uncertain significance, 4 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1065412	NM_014396.4(VPS41):c.450+1G>T	VPS41	Pathogenic	no assertion criteria provided
1175719	NM_014396.4(VPS41):c.2372G>T (p.Cys791Phe)	VPS41	Pathogenic	no assertion criteria provided
1175720	NM_014396.4(VPS41):c.1423-2A>G	VPS41	Pathogenic	no assertion criteria provided
1175722	NM_014396.4(VPS41):c.1898G>C (p.Arg633Pro)	VPS41	Pathogenic	no assertion criteria provided
1252063	NM_001673.5(ASNS):c.1211G>A (p.Arg404His)	ASNS	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1175718	NM_014396.4(VPS41):c.853T>C (p.Ser285Pro)	VPS41	Likely pathogenic	criteria provided, single submitter
1175721	NM_014396.4(VPS41):c.1984C>T (p.Arg662Ter)	VPS41	Likely pathogenic	criteria provided, single submitter
2431434	NM_014396.4(VPS41):c.1999C>T (p.Arg667Ter)	VPS41	Likely pathogenic	criteria provided, single submitter
4076109	NM_014396.4(VPS41):c.385-2A>G	VPS41	Likely pathogenic	criteria provided, single submitter
4076110	NM_014396.4(VPS41):c.1247G>A (p.Arg416His)	VPS41	Likely pathogenic	criteria provided, single submitter
4845792	NM_014396.4(VPS41):c.1836C>A (p.Tyr612Ter)	VPS41	Likely pathogenic	criteria provided, single submitter
2320801	NM_014396.4(VPS41):c.1615G>A (p.Val539Ile)	VPS41	Uncertain significance	criteria provided, multiple submitters, no conflicts
2568472	NM_014396.4(VPS41):c.2411C>G (p.Ala804Gly)	VPS41	Uncertain significance	criteria provided, multiple submitters, no conflicts
3766708	NM_014396.4(VPS41):c.1622A>G (p.Gln541Arg)	VPS41	Uncertain significance	criteria provided, single submitter
4076111	NM_014396.4(VPS41):c.409G>A (p.Val137Met)	VPS41	Uncertain significance	criteria provided, single submitter
4076112	NM_014396.4(VPS41):c.881C>T (p.Thr294Met)	VPS41	Uncertain significance	criteria provided, single submitter
4277843	NM_014396.4(VPS41):c.190T>G (p.Tyr64Asp)	VPS41	Uncertain significance	criteria provided, single submitter
4278050	NM_014396.4(VPS41):c.239T>C (p.Phe80Ser)	VPS41	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
VPS41	Strong	Autosomal recessive	spinocerebellar ataxia, autosomal recessive 29	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VPS41	Orphanet:95434	Autosomal recessive cerebellar ataxia-movement disorder syndrome
ASNS	Orphanet:391376	Congenital microcephaly-severe encephalopathy-progressive cerebral atrophy 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
VPS41	HGNC:12713	ENSG00000006715	P49754	Vacuolar protein sorting-associated protein 41 homolog	gencc,clinvar
ASNS	HGNC:753	ENSG00000070669	P08243	Asparagine synthetase [glutamine-hydrolyzing]	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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: 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
Enzyme (other)	1	6.0×	0.228
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VPS41	Transcription factor	no		Clathrin_H-chain/VPS_repeat, Znf_RING, TPR-like_helical_dom_sf
ASNS	Enzyme (other)	yes	6.3.5.4	Asn_synthase, Asn_synth_AEB, Rossmann-like_a/b/a_fold

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
adrenal tissue	1
calcaneal tendon	1
gall bladder	1
cerebellar cortex	1
cerebellar hemisphere	1
cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VPS41	275	ubiquitous	marker	calcaneal tendon, adrenal tissue, gall bladder
ASNS	143	ubiquitous	marker	cerebellar hemisphere, cerebellar cortex, cerebellum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VPS41	1,068
ASNS	290

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ASNS	P08243	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
VPS41	P49754	86.63

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. 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
Aspartate and asparagine metabolism	1	519.1×	0.008	ASNS
SARS-CoV-2 modulates autophagy	1	519.1×	0.008	VPS41
PERK regulates gene expression	1	407.9×	0.008	ASNS
Response of EIF2AK1 (HRI) to heme deficiency	1	356.9×	0.008	ASNS
ATF4 activates genes in response to endoplasmic reticulum stress	1	203.9×	0.011	ASNS
Unfolded Protein Response (UPR)	1	178.4×	0.011	ASNS
Cellular response to starvation	1	82.8×	0.021	ASNS
Response of EIF2AK4 (GCN2) to amino acid deficiency	1	55.4×	0.027	ASNS
Metabolism of amino acids and derivatives	1	33.8×	0.039	ASNS
Cellular responses to stress	1	18.4×	0.064	ASNS
Cellular responses to stimuli	1	15.7×	0.068	ASNS
Metabolism	1	5.8×	0.165	ASNS

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
L-asparagine biosynthetic process	1	8426.0×	0.002	ASNS
obsolete asparagine biosynthetic process	1	4213.0×	0.002	ASNS
Golgi vesicle transport	1	766.0×	0.004	VPS41
protein targeting to vacuole	1	648.1×	0.004	VPS41
regulation of SNARE complex assembly	1	648.1×	0.004	VPS41
endosomal vesicle fusion	1	561.7×	0.004	VPS41
late endosome to lysosome transport	1	495.6×	0.004	VPS41
positive regulation of mitotic cell cycle	1	234.1×	0.007	ASNS
endosome to lysosome transport	1	168.5×	0.008	VPS41
cellular response to glucose starvation	1	168.5×	0.008	ASNS
macroautophagy	1	120.4×	0.011	VPS41
cellular response to starvation	1	96.8×	0.012	VPS41
vesicle-mediated transport	1	48.1×	0.022	VPS41
negative regulation of apoptotic process	1	17.4×	0.057	ASNS

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
VPS41	0	0
ASNS	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
ASNS	27	Binding:27

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ASNS	6.3.5.4	asparagine synthase (glutamine-hydrolysing)

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	1	ASNS
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	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)
VPS41	0	—
ASNS	27	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.