Striatonigral degeneration, childhood-onset

Summary

Striatonigral degeneration, childhood-onset (MONDO:0014889) is a disease caused by VAC14 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: VAC14 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 25

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	striatonigral degeneration, childhood-onset
Mondo ID	MONDO:0014889
OMIM	617054
Orphanet	497906
UMLS	C4310743
MedGen	934710
GARD	0017918
Is cancer (heuristic)	no

Also known as: childhood-onset basal ganglia degeneration syndrome · Lenk-Ploski syndrome · SNDC · striatonigral Degeneration, childhood-onset · striatonigral degeneration, childhood-onset; SNDC

Data availability: 25 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › synucleinopathy › multiple system atrophy › striatonigral degeneration › striatonigral degeneration, childhood-onset

Related subtypes (2): striatal degeneration, autosomal dominant, familial infantile bilateral striatal necrosis

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

25 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 6 benign, 5 pathogenic, 2 conflicting classifications of pathogenicity, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
253140	NM_018052.5(VAC14):c.1271G>T (p.Trp424Leu)	VAC14	Pathogenic	no assertion criteria provided
253141	NM_018052.5(VAC14):c.1528+1G>A	VAC14	Pathogenic	no assertion criteria provided
253142	NM_018052.5(VAC14):c.1744G>T (p.Ala582Ser)	VAC14	Pathogenic	no assertion criteria provided
253143	NM_018052.5(VAC14):c.1748C>T (p.Ser583Leu)	VAC14	Pathogenic	no assertion criteria provided
397536	NM_018052.5(VAC14):c.923T>A (p.Leu308Ter)	VAC14	Pathogenic	criteria provided, multiple submitters, no conflicts
1805191	NM_018052.5(VAC14):c.104+2T>G	VAC14	Likely pathogenic	criteria provided, single submitter
2664898	NM_018052.5(VAC14):c.921C>A (p.Cys307Ter)	VAC14	Likely pathogenic	criteria provided, single submitter
1032018	NM_018052.5(VAC14):c.1723C>T (p.Arg575Trp)	VAC14	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
638191	NM_018052.5(VAC14):c.2005G>T (p.Val669Leu)	VAC14	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030622	NM_018052.5(VAC14):c.2015T>C (p.Ile672Thr)	VAC14	Uncertain significance	criteria provided, single submitter
1332727	NM_018052.5(VAC14):c.1927C>T (p.Arg643Trp)	VAC14	Uncertain significance	criteria provided, single submitter
1339182	NM_018052.5(VAC14):c.1867C>T (p.Arg623Cys)	VAC14	Uncertain significance	criteria provided, multiple submitters, no conflicts
2438507	NM_018052.5(VAC14):c.1063G>A (p.Asp355Asn)	VAC14	Uncertain significance	criteria provided, single submitter
3362731	NM_018052.5(VAC14):c.412G>A (p.Gly138Arg)	VAC14	Uncertain significance	criteria provided, multiple submitters, no conflicts
3393254	NM_018052.5(VAC14):c.541C>G (p.Arg181Gly)	VAC14	Uncertain significance	criteria provided, single submitter
3772667	NM_018052.5(VAC14):c.607G>C (p.Glu203Gln)	VAC14	Uncertain significance	criteria provided, single submitter
3772668	NM_018052.5(VAC14):c.507C>A (p.Asn169Lys)	VAC14	Uncertain significance	criteria provided, single submitter
4080985	NM_018052.5(VAC14):c.1700A>G (p.His567Arg)	VAC14	Uncertain significance	criteria provided, single submitter
2438506	NM_018052.5(VAC14):c.1339C>G (p.Leu447Val)	VAC14-AS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1183222	NM_018052.5(VAC14):c.1306-27G>A	VAC14	Benign	criteria provided, multiple submitters, no conflicts
1221543	NM_018052.5(VAC14):c.424-18T>C	VAC14	Benign	criteria provided, multiple submitters, no conflicts
1235270	NM_018052.5(VAC14):c.2115G>T (p.Pro705=)	VAC14	Benign	criteria provided, multiple submitters, no conflicts
1260691	NM_018052.5(VAC14):c.811+43G>A	VAC14	Benign	criteria provided, multiple submitters, no conflicts
1269382	NM_018052.5(VAC14):c.1306-7C>T	VAC14	Benign	criteria provided, multiple submitters, no conflicts
1276596	NM_018052.5(VAC14):c.1662-47C>G	VAC14	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
VAC14	Strong	Autosomal recessive	striatonigral degeneration, childhood-onset	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VAC14	Orphanet:3472	Yunis-Varon syndrome
VAC14	Orphanet:497906	Childhood-onset basal ganglia degeneration syndrome

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
VAC14	HGNC:25507	ENSG00000103043	Q08AM6	Protein VAC14 homolog	gencc,clinvar
VAC14-AS1	HGNC:48605	ENSG00000214353		VAC14 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VAC14	Protein VAC14 homolog	Scaffold protein component of the PI(3,5)P2 regulatory complex which regulates both the synthesis and turnover of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VAC14	Other/Unknown	no		ARM-like, ARM-type_fold, VAC14_Fig4p-bd
VAC14-AS1	Other/Unknown	no

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
hindlimb stylopod muscle	1
primordial germ cell in gonad	1
stromal cell of endometrium	1
male germ line stem cell (sensu Vertebrata) in testis	1
nucleus accumbens	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VAC14	233	ubiquitous	marker	stromal cell of endometrium, primordial germ cell in gonad, hindlimb stylopod muscle
VAC14-AS1	164	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, right hemisphere of cerebellum, nucleus accumbens

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VAC14	2,357
VAC14-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VAC14	Q08AM6	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Synthesis of PIPs at the late endosome membrane	1	951.7×	0.002	VAC14
Synthesis of PIPs at the early endosome membrane	1	713.8×	0.002	VAC14
Synthesis of PIPs at the Golgi membrane	1	634.4×	0.002	VAC14

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of postsynaptic neurotransmitter receptor internalization	1	624.1×	0.004	VAC14
phosphatidylinositol biosynthetic process	1	366.4×	0.004	VAC14
signal transduction	1	16.1×	0.062	VAC14

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
VAC14	0	0
VAC14-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
VAC14	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	VAC14, VAC14-AS1

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)
VAC14	1	—
VAC14-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.