VPS37A

Chr 8AR

VPS37A subunit of ESCRT-I

Also known as: HCRP1, PQBP2, SPG53

NCBI Gene: 137492ENSG00000155975UniProt: Q8NEZ2

This gene belongs to the VPS37 family, and encodes a component of the ESCRT-I (endosomal sorting complex required for transport I) protein complex, required for the sorting of ubiquitinated transmembrane proteins into internal vesicles of multivesicular bodies. Expression of this gene is downregulated in hepatocellular carcinoma, and mutations in this gene are associated with autosomal recessive spastic paraplegia-53. A related pseudogene has been identified on chromosome 5. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2012]

Primary Disease Associations & Inheritance

Spastic paraplegia 53, autosomal recessiveMIM #614898
AR
416
ClinVar variants
81
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— VPS37A
🧬
Gene-Disease Validity (ClinGen)
complex hereditary spastic paraplegia · ARLimited

Limited evidence — not for standalone diagnostic reporting

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
81 Pathogenic / Likely Pathogenic· 210 VUS of 416 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.
0.72LOEUF
pLI 0.001
Z-score 2.53
OE 0.41 (0.25–0.72)
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.
-0.88Z-score
OE missense 1.18 (1.06–1.31)
235 obs / 199.8 exp
Tolerant

Tolerant to missense variation

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.0.41 (0.25–0.72)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.18 (1.06–1.31)
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.1.27
0≤1.21.6
LoF obs/exp: 9 / 21.7Missense obs/exp: 235 / 199.8Syn Z: -1.82

ClinVar Variant Classifications

416 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic77
Likely Pathogenic4
VUS210
Likely Benign94
Benign27
Conflicting4
77
Pathogenic
4
Likely Pathogenic
210
VUS
94
Likely Benign
27
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
76
0
77
Likely Pathogenic
0
0
4
0
4
VUS
3
187
17
3
210
Likely Benign
2
7
51
34
94
Benign
0
1
24
2
27
Conflicting
—4
Total519617239416

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

View in ClinVar →

Protein Context — Lollipop Plot

VPS37A · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Spastic paraplegia 53, autosomal recessive

MIM #614898

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
VPS37A Activates the Autophagy-Lysosomal Pathway for TNFR1 Degradation and Induces NF-κB-Regulated Cell Death under Metabolic Stress in Colorectal Cancer.
Liu C et al.·Oncol Res
2025
VPS37A directs ESCRT recruitment for phagophore closure.
Takahashi Y et al.·J Cell Biol
2019
A founder mutation in Vps37A causes autosomal recessive complex hereditary spastic paraparesis.
Zivony-Elboum Y et al.·J Med Genet
2012
Coping with brain amyloid: genetic heterogeneity and cognitive resilience to Alzheimer's pathophysiology.
Ramanan VK et al.·Acta Neuropathol Commun
2021
Blocking autophagosome closure manifests the roles of mammalian Atg8-family proteins in phagophore formation and expansion during nutrient starvation.
Bui V et al.·Autophagy
2025
Loss of HCRP1 leads to upregulation of PD-L1 via STAT3 activation and is of prognostic significance in EGFR-dependent cancer.
Tomasich E et al.·Transl Res
2021
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