Pontocerebellar hypoplasia, type 13

Summary

Pontocerebellar hypoplasia, type 13 (MONDO:0032831) is a disease caused by VPS53 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: VPS53 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 10

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	pontocerebellar hypoplasia, type 13
Mondo ID	MONDO:0032831
OMIM	618606
Orphanet	613267
DOID	DOID:0112332
UMLS	C5231425
MedGen	1684708
GARD	0018031
Is cancer (heuristic)	no

Also known as: PCH13 · PONTOCEREBELLAR HYPOPLASIA, TYPE 13

Data availability: 10 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system malformation › pontocerebellar hypoplasia › pontocerebellar hypoplasia, type 13

Related subtypes (20): pontocerebellar hypoplasia type 4, pontocerebellar hypoplasia type 3, pontocerebellar hypoplasia type 5, pontocerebellar hypoplasia type 6, pontocerebellar hypoplasia type 8, pontocerebellar hypoplasia type 7, pontocerebellar hypoplasia type 10, pontocerebellar hypoplasia type 9, pontocerebellar hypoplasia type 2E, pontocerebellar hypoplasia type 1, pontocerebellar hypoplasia type 2, pontocerebellar hypoplasia, type 14, pontocerebellar hypoplasia, type 15, pontocerebellar hypoplasia, type 1E, pontocerebellar hypoplasia, type 1F, pontocerebellar hypoplasia, type 16, pontocerebellar hypoplasia, IIA 17, pontocerebellar hypoplasia, type 12, pontocerebellar hypoplasia, type 11, pontocerebellar hypoplasia, type 1D

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, 3 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
691588	NM_013265.4(VPS51):c.2232del (p.Asp745fs)	VPS51	Pathogenic	no assertion criteria provided
691589	NM_013265.4(VPS51):c.1468C>T (p.Arg490Cys)	VPS51	Pathogenic	criteria provided, single submitter
691590	NM_013265.4(VPS51):c.1421_1423del (p.Phe474del)	VPS51	Pathogenic	no assertion criteria provided
1698446	NM_013265.4(VPS51):c.419CCA[1] (p.Thr141del)	VPS51	Uncertain significance	criteria provided, single submitter
1703249	NM_013265.4(VPS51):c.1878+42G>A	VPS51	Uncertain significance	no assertion criteria provided
2366203	NM_013265.4(VPS51):c.32C>T (p.Pro11Leu)	VPS51	Uncertain significance	criteria provided, multiple submitters, no conflicts
3376439	NM_013265.4(VPS51):c.868G>C (p.Glu290Gln)	VPS51	Uncertain significance	criteria provided, single submitter
3780788	NM_013265.4(VPS51):c.2144_2145del (p.Val715fs)	VPS51	Uncertain significance	criteria provided, single submitter
3892861	NM_013265.4(VPS51):c.1173_1182del (p.Ala392fs)	VPS51	Uncertain significance	criteria provided, single submitter
4292967	NM_013265.4(VPS51):c.1443+5G>A	VPS51	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
VPS53	Strong	Autosomal recessive	pontocerebellar hypoplasia, type 13	3
VPS51	Moderate	Autosomal recessive	pontocerebellar hypoplasia, type 13	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VPS53	Orphanet:247198	Progressive cerebello-cerebral atrophy

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
VPS51	HGNC:1172	ENSG00000149823	Q9UID3	Vacuolar protein sorting-associated protein 51 homolog	gencc,clinvar
VPS53	HGNC:25608	ENSG00000141252	Q5VIR6	Vacuolar protein sorting-associated protein 53 homolog	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VPS51	Vacuolar protein sorting-associated protein 51 homolog	Acts as a component of the GARP complex that is involved in retrograde transport from early and late endosomes to the trans-Golgi network (TGN).
VPS53	Vacuolar protein sorting-associated protein 53 homolog	Acts as a component of the GARP complex that is involved in retrograde transport from early and late endosomes to the trans-Golgi network (TGN).

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)
VPS51	Other/Unknown	no		Vps51, Cullin_repeat-like_dom_sf
VPS53	Other/Unknown	no		Vps53_N, Vps53_C, Vps53_C_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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
apex of heart	1
body of pancreas	1
cortical plate	1
bone marrow cell	1
stromal cell of endometrium	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VPS51	290	ubiquitous	marker	body of pancreas, cortical plate, apex of heart
VPS53	140	ubiquitous	yes	sural nerve, bone marrow cell, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VPS53	1,921
VPS51	1,658

Intra-cohort edges

A	B	Sources
VPS51	VPS53	biogrid_interaction, intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VPS51	Q9UID3	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
VPS53	Q5VIR6	80.86

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Retrograde transport at the Trans-Golgi-Network	2	219.6×	2e-05	VPS51, VPS53

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
vesicle-mediated cholesterol transport	2	2808.7×	1e-06	VPS51, VPS53
lysosomal transport	2	702.2×	1e-05	VPS51, VPS53
endocytic recycling	2	267.5×	5e-05	VPS51, VPS53
retrograde transport, endosome to Golgi	2	205.5×	6e-05	VPS51, VPS53
Golgi vesicle transport	1	766.0×	0.003	VPS51
brain morphogenesis	1	366.4×	0.005	VPS51
protein targeting to lysosome	1	312.1×	0.005	VPS53
protein targeting	1	183.2×	0.007	VPS51
Golgi organization	1	66.9×	0.018	VPS51
autophagy	1	55.1×	0.020	VPS51
protein transport	1	21.9×	0.045	VPS51

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
VPS51	0	0
VPS53	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
VPS51	1	Binding:1

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	VPS51, VPS53

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)
VPS51	1	—
VPS53	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.