GeneBe

VPS53

protein-coding

VPS53 subunit of GARP complex, the group of Golgi associated retrograde protein (GARP) complex|Endosome-associated recycling protein (EARP) complex

Gene summary

Involved in endocytic recycling and retrograde transport, endosome to Golgi. Acts upstream of or within lysosomal transport. Located in several cellular components, including Golgi apparatus; perinuclear region of cytoplasm; and recycling endosome. Part of EARP complex and GARP complex. Implicated in pontocerebellar hypoplasia type 2E. [provided by Alliance of Genome Resources, Jul 2025]

MANE transcript

NM_001128159.3

Inheritance

AR

ClinVar variants

P:20U:134B:231

Top phenotype

Pontocerebellar hypoplasia, type 2E

gnomAD constraint

pLI —, LoF o/e 0.42

Max pathogenic AF

—

Genomic locus

chr17:508,503-721,717

External References & Databases

Ensembl (ENSG00000141252)NCBI Gene (55275)OMIM (615850)HGNC:25608GenCCUniProt (Q5VIR6)AlphaFoldClinVar (VPS53)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~213.2 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

pontocerebellar hypoplasia, type 13STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032831

Submitter: Labcorp Genetics (formerly Invitae)

pontocerebellar hypoplasia type 2EDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014370

Submitter: G2P

progressive cerebello-cerebral atrophySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016589

Submitter: Orphanet

pontocerebellar hypoplasia type 2ESTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014370

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Pontocerebellar hypoplasia, type 2EAR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 24577744Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to VPS53 variants in ClinVar

9 Conditions Cataloged
not providedTotal: 484
Inborn genetic diseasesTotal: 100
not specifiedTotal: 32
Pontocerebellar hypoplasia type 2ETotal: 28
VPS53-related disorderTotal: 13
Pontocerebellar hypoplasia type 2ATotal: 1
Pontoneocerebellar hypoplasiaTotal: 1
MicrocephalyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001128159.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
2
clinvar
220
clinvar
5
clinvar
 227
missense
2
clinvar
2
clinvar
122
clinvar
5
clinvar
1
clinvar
 132
nonsense
6
clinvar
2
clinvar
 8
start loss
1
clinvar
 1
frameshift
5
clinvar
3
clinvar
 8
splice donor/acceptor (+/-2bp)
5
clinvar
4
clinvar
 9
Total2181342256385

Highest pathogenic variant AF is 0.0000632105

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 88 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001128159.3RefSeqNP_001121631.122MANE Select
ENST00000437048.7EnsemblENSP00000401435.222MANE Select
NM_001366253.2RefSeqNP_001353182.119Standard
NM_001366254.2RefSeqNP_001353183.113Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Vesicle-mediated transport
  • Membrane Trafficking
  • Retrograde transport at the Trans-Golgi-Network
  • Intra-Golgi and retrograde Golgi-to-ER traffic

Biological Process

  • lysosomal transport
  • protein transport
  • endocytic recycling
  • retrograde transport, endosome to Golgi

Molecular Function

  • protein binding

Cellular Component

  • GARP complex
  • Golgi apparatus
  • cytosol
  • endosome membrane
  • membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000437048
Coding exons
22
Length
213050
Individuals with no LoFs
125689
Homozygous LoFs
0
Heterozygous LoFs
59
Defined
125748
p
0.000235
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.583744700.7950.00002725463
Missense (PolyPhen)80135.830.588991707
Synonymous-0.2841901851.030.00001171591
Loss of Function3.702047.50.4210.00000262532

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000250.00025rare
Latino/Admixed American0.000170.00017rare
Ashkenazi Jewish0.0000990.000099rare
East Asian0.000380.00038rare
Finnish0.000650.00065rare
European (Non-Finnish)0.000180.00018rare
South Asian0.000200.00020rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Acts as component of the GARP complex that is involved in retrograde transport from early and late endosomes to the trans-Golgi network (TGN). The GARP complex is required for the maintenance of the cycling of mannose 6-phosphate receptors between the TGN and endosomes, this cycling is necessary for proper lysosomal sorting of acid hydrolases such as CTSD (PubMed:15878329, PubMed:18367545). Acts as component of the EARP complex that is involved in endocytic recycling. The EARP complex associates with Rab4-positive endosomes and promotes recycling of internalized transferrin receptor (TFRC) to the plasma membrane (PubMed:25799061). {ECO:0000269|PubMed:15878329, ECO:0000269|PubMed:18367545, ECO:0000269|PubMed:25799061}.;
Disease
DISEASE: Pontocerebellar hypoplasia 2E (PCH2E) [MIM:615851]: A neurodegenerative disorder characterized by progressive cerebello- cerebral atrophy, profound mental retardation, progressive microcephaly, spasticity, and early-onset epilepsy. {ECO:0000269|PubMed:24577744}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool
0.843
RVIS EVS
-1.22
RVIS percentile EVS
5.67

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
E
Indispensability pred.
N
Indispensability score
0.348

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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