pontocerebellar hypoplasia type 2E

disease

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Also known as non-syndromic pontocerebellar hypoplasia caused by mutation in VPS53PCH2Epontocerebellar hypoplasia, type 2EVPS53 non-syndromic pontocerebellar hypoplasia

Summary

pontocerebellar hypoplasia type 2E (MONDO:0014370) is a disease caused by VPS53 (GenCC Strong), with 1 cohort gene.

At a glance

Causal gene: VPS53 (GenCC Strong)
Cohort genes: 1
ClinVar variants: 42

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pontocerebellar hypoplasia type 2E
Mondo ID	MONDO:0014370
OMIM	615851
DOID	DOID:0060271
UMLS	C4014488
MedGen	862925
GARD	0018348
Is cancer (heuristic)	no

Also known as: non-syndromic pontocerebellar hypoplasia caused by mutation in VPS53 · PCH2E · pontocerebellar hypoplasia type 2E · pontocerebellar hypoplasia, type 2E · VPS53 non-syndromic pontocerebellar hypoplasia

Data availability: 42 ClinVar variants · 1 GenCC gene-disease record.

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 2E

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

42 retrieved; paginated sample, class counts are floors:

15 benign, 12 likely pathogenic, 9 uncertain significance, 3 conflicting classifications of pathogenicity, 1 pathogenic, 1 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
139444	NM_001128159.3(VPS53):c.2084A>G (p.Gln695Arg)	VPS53	Pathogenic	criteria provided, multiple submitters, no conflicts
139445	NM_001128159.3(VPS53):c.1556+5G>A	VPS53	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3582205	NM_001128159.3(VPS53):c.1642G>T (p.Glu548Ter)	LOC126862456	Likely pathogenic	criteria provided, single submitter
3582153	NM_001128159.3(VPS53):c.1972del (p.Ser658fs)	VPS53	Likely pathogenic	criteria provided, single submitter
3582154	NM_001128159.3(VPS53):c.1915del (p.Thr639fs)	VPS53	Likely pathogenic	criteria provided, single submitter
3582334	NM_001128159.3(VPS53):c.840G>A (p.Trp280Ter)	VPS53	Likely pathogenic	criteria provided, single submitter
3582335	NM_001128159.3(VPS53):c.800_801del (p.Glu267fs)	VPS53	Likely pathogenic	criteria provided, single submitter
3582336	NM_001128159.3(VPS53):c.687+1G>A	VPS53	Likely pathogenic	criteria provided, single submitter
3582337	NM_001128159.3(VPS53):c.609-1G>T	VPS53	Likely pathogenic	criteria provided, single submitter
3582399	NM_001128159.3(VPS53):c.238C>T (p.Arg80Ter)	VPS53	Likely pathogenic	criteria provided, single submitter
3582400	NM_001128159.3(VPS53):c.168+2T>G	VPS53	Likely pathogenic	criteria provided, single submitter
557943	NM_001128159.3(VPS53):c.1516C>T (p.Arg506Ter)	VPS53	Likely pathogenic	no assertion criteria provided
817131	NM_001128159.3(VPS53):c.300_301dup (p.Gln101fs)	VPS53	Likely pathogenic	criteria provided, multiple submitters, no conflicts
818227	NM_001128159.3(VPS53):c.692C>T (p.Pro231Leu)	VPS53	Likely pathogenic	no assertion criteria provided
1696170	NM_001128159.3(VPS53):c.869G>A (p.Trp290Ter)	VPS53	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
403603	NM_001128159.3(VPS53):c.1750C>T (p.Arg584Ter)	VPS53	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
554119	NM_001128159.3(VPS53):c.1312_1313+2del	VPS53	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029110	NM_001128159.3(VPS53):c.2006A>G (p.Lys669Arg)	VPS53	Uncertain significance	criteria provided, single submitter
1029111	NM_001128159.3(VPS53):c.2329G>C (p.Gly777Arg)	VPS53	Uncertain significance	criteria provided, single submitter
1029112	NM_001128159.3(VPS53):c.2365C>G (p.Leu789Val)	VPS53	Uncertain significance	criteria provided, single submitter
1029113	NM_001128159.3(VPS53):c.2420T>C (p.Leu807Pro)	VPS53	Uncertain significance	criteria provided, single submitter
1032644	NM_001128159.3(VPS53):c.959T>G (p.Phe320Cys)	VPS53	Uncertain significance	criteria provided, single submitter
4277906	NM_001128159.3(VPS53):c.373G>A (p.Val125Met)	VPS53	Uncertain significance	criteria provided, single submitter
444390	NM_001128159.3(VPS53):c.584C>T (p.Pro195Leu)	VPS53	Uncertain significance	criteria provided, multiple submitters, no conflicts
551839	NM_001128159.3(VPS53):c.2347C>T (p.Gln783Ter)	VPS53	Uncertain significance	no assertion criteria provided
984594	NM_001128159.3(VPS53):c.1247C>A (p.Pro416Gln)	VPS53	Uncertain significance	criteria provided, multiple submitters, no conflicts
1185378	NM_001128159.3(VPS53):c.1557-30T>C	LOC126862456	Benign	criteria provided, multiple submitters, no conflicts
1185461	NM_001128159.3(VPS53):c.1117-26T>C	LOC126862457	Benign	criteria provided, multiple submitters, no conflicts
670839	NM_001128159.3(VPS53):c.1218+57G>C	LOC126862457	Benign	criteria provided, multiple submitters, no conflicts
670860	NM_001128159.3(VPS53):c.1117-91C>G	LOC126862457	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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

Orphanet rare-disease linkage (cohort genes)

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

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
VPS53	HGNC:25608	ENSG00000141252	Q5VIR6	Vacuolar protein sorting-associated protein 53 homolog	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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: 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VPS53	Other/Unknown	no		Vps53_N, Vps53_C, Vps53_C_sf

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
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
VPS53	140	ubiquitous	yes	sural nerve, bone marrow cell, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VPS53	1,921

Structural data

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

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 1 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
Retrograde transport at the Trans-Golgi-Network	1	219.6×	0.005	VPS53

GO biological processes by enrichment

GO term	Cohort genes	Fold	FDR	Sample cohort genes
vesicle-mediated cholesterol transport	1	2808.7×	0.002	VPS53
lysosomal transport	1	702.2×	0.003	VPS53
protein targeting to lysosome	1	624.1×	0.003	VPS53
endocytic recycling	1	267.5×	0.005	VPS53
retrograde transport, endosome to Golgi	1	205.5×	0.005	VPS53

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
VPS53	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	1	VPS53

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
VPS53	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: VPS53