VPS37A

protein-coding

VPS37A subunit of ESCRT-I, the group of ESCRT-I

Gene summary

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]

Previous symbols:

PQBP2

MANE transcript

NM_152415.3

Inheritance

ClinVar variants

P:1U:128B:40

Top phenotype

Spastic paraplegia 53, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.41

Max pathogenic AF

—

Genomic locus

chr8:17,246,931-17,302,427

External References & Databases

Ensembl (ENSG00000155975)

Transcript & Mutation Effects

hg38 • Region Span ~55.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex hereditary spastic paraplegiaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0015150

Submitter: ClinGen

*VPS37A* was first reported in relation to autosomal recessive complex hereditary spastic paraplegia in 2012 (Zivony-Elboum et al., PMID: 22717650). At the time of this review, this publication remained the only publication discussing clinical variants. Zivony-Elboum et al. described two consanguineous Arab Moslem families with the same homozygous variant segregating with disease in both families; haplotype analysis performed indicated a founder effect (PMID: 22717650). Both probands were found to have mild intellectual disability, spastic paraparesis, kyphosis, small joint hypermobility, clonus, and delayed gross motor development. This gene-disease relationship is also supported by a rescue study in zebrafish (PMID: 22717650). In summary, there is limited evidence supporting this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Cerebral Palsy GCEP on the meeting date March 6, 2025 (SOP Version 11).

hereditary spastic paraplegia 53LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013962

Submitter: Ambry Genetics

hereditary spastic paraplegia 53MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013962

Submitter: PanelApp Australia

hereditary spastic paraplegia 53LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013962

Submitter: Labcorp Genetics (formerly Invitae)

hereditary spastic paraplegia 53SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013962

Submitter: Orphanet

Clinical Genomic Database (CGD)

Spastic paraplegia 53, autosomal recessiveAR

Manifestation: Neurologic

Intervention: General

Rationale: The use of botulinum has been described as beneficial for treating spasticity in some individuals, though the advantage of genetic diagnosis is unclear; 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: 22717650

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to VPS37A variants in ClinVar

6 Conditions Cataloged

Hereditary spastic paraplegia 53Total: 150

not specifiedTotal: 75

not providedTotal: 34

Hereditary spastic paraplegiaTotal: 16

VPS37A-related disorderTotal: 6

Idiopathic transverse myelitisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_152415.3. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar	35 clinvar		40
missense	1 clinvar		120 clinvar	4 clinvar	1 clinvar	126
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	1	0	128	39	1	169

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 98 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_152415.3	RefSeq	NP_689628.2	11	MANE Select
ENST00000324849.9	Ensembl	ENSP00000318629.4	11	MANE Select
NM_001145152.2	RefSeq	NP_001138624.1	10	Standard
NM_001363167.1	RefSeq	NP_001350096.1	11	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
vps37a	Danio rerio	Structure: whole organism Quality: decreased mobility abnormal

Gene / Model

Organism

Observed Phenotype

vps37a

Danio rerio

Structure: whole organism

Quality: decreased mobility

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Endocytosis - Homo sapiens (human)
Disease
Vesicle-mediated transport
Membrane Trafficking
Assembly Of The HIV Virion

Biological Process

protein targeting to membrane
protein targeting to vacuole
protein transport
endosomal transport
macroautophagy

Molecular Function

protein binding

Cellular Component

ESCRT I complex
nucleoplasm
centrosome
cytosol
endosome membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000324849
Coding exons: 11
Length: 55857
Individuals with no LoFs: 125721
Homozygous LoFs: 0
Heterozygous LoFs: 16
Defined: 125737
p: 0.0000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.885	235	200	1.18	0.00000897	2603
Missense (PolyPhen)		37	48.493	0.76299		678
Synonymous	-1.82	92	72.3	1.27	0.00000352	731
Loss of Function	2.53	9	21.7	0.414	0.00000102	276

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000088	0.000087	rare
Ashkenazi Jewish	0.00020	0.000099	rare
East Asian	0.00011	0.00011	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0.00010	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the ESCRT-I complex, a regulator of vesicular trafficking process. Required for the sorting of endocytic ubiquitinated cargos into multivesicular bodies. May be involved in cell growth and differentiation. {ECO:0000269|PubMed:15240819}.;

Intolerance Scores

LoFtool: 0.592
RVIS EVS: -0.54
RVIS percentile EVS: 20.54

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.904

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium