VPS53

Chr 17AR

VPS53 subunit of GARP complex

Also known as: HCCS1, PCH2E, hVps53L, pp13624

NCBI Gene: 55275ENSG00000141252UniProt: Q5VIR6

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]

Primary Disease Associations & Inheritance

Pontocerebellar hypoplasia, type 2EMIM #615851
AR
843
ClinVar variants
23
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— VPS53
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
23 Pathogenic / Likely Pathogenic· 84 VUS of 843 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.61LOEUF
pLI 0.000
Z-score 3.70
OE 0.42 (0.29–0.61)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.58Z-score
OE missense 0.80 (0.73–0.87)
374 obs / 470.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.42 (0.29–0.61)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.80 (0.73–0.87)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.03
0≤1.21.6
LoF obs/exp: 20 / 47.5Missense obs/exp: 374 / 470.3Syn Z: -0.28

ClinVar Variant Classifications

843 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12
Likely Pathogenic11
VUS84
Likely Benign370
Benign5
12
Pathogenic
11
Likely Pathogenic
84
VUS
370
Likely Benign
5
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
12
0
12
Likely Pathogenic
6
1
4
0
11
VUS
1
68
15
0
84
Likely Benign
1
1
172
196
370
Benign
0
0
3
2
5
Total870206198482

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

VPS53 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

VPS53-related progressive cerebello-cerebral atrophy

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Pontocerebellar hypoplasia, type 2E

MIM #615851

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Extensive germline-somatic interplay contributes to prostate cancer progression through HNF1B co-option of TMPRSS2-ERG.
Giannareas N et al.·Nat Commun
2022
VPS53 gene is associated with a new phenotype of complicated hereditary spastic paraparesis.
Hausman-Kedem M et al.·Neurogenetics
2019Case report
Clinical and molecular characteristics of paediatric mature B-cell acute lymphocytic leukaemia and non-Hodgkin lymphoma with bone marrow involvement: A joint study between the CCCG leukaemia and lymphoma groups.
Zhao J et al.·Br J Haematol
2025
Hepatic manifestations in VPS53-related pontocerebellar hypoplasia type 2E: A case report.
Mouchez A et al.·Eur J Med Genet
2025Case report
The landscape of RNA polymerase II-associated chromatin interactions in prostate cancer.
Ramanand SG et al.·J Clin Invest
2020
Biallelic variants in VPS50 cause a neurodevelopmental disorder with neonatal cholestasis.
Schneeberger PE et al.·Brain
2021Case report
Complex structural variation and nonsense variant in trans cause VPS50-related disorder.
Hecher L et al.·J Med Genet
2024Case report
Novel variants underlying autosomal recessive intellectual disability in Pakistani consanguineous families.
Ilyas M et al.·BMC Med Genet
2020Case report
Progressive cerebello-cerebral atrophy and progressive encephalopathy with edema, hypsarrhythmia and optic atrophy may be allelic syndromes.
Hady-Cohen R et al.·Eur J Paediatr Neurol
2018Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools