VPS52

protein-coding

VPS52 subunit of GARP complex, the group of Golgi associated retrograde protein (GARP) complex|Endosome-associated recycling protein (EARP) complex

Gene summary

This gene encodes a protein that is similar to the yeast suppressor of actin mutations 2 gene. The yeast protein forms a subunit of the tetrameric Golgi-associated retrograde protein complex that is involved in vesicle trafficking from from both early and late endosomes, back to the trans-Golgi network. This gene is located on chromosome 6 in a head-to-head orientation with the gene encoding ribosomal protein S18. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

Previous symbols:

SACM2L

MANE transcript

NM_022553.6

Inheritance

ClinVar variants

U:94B:2

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.32

Max pathogenic AF

—

Genomic locus

chr6:33,250,272-33,272,047

External References & Databases

Ensembl (ENSG00000223501)

Transcript & Mutation Effects

hg38 • Region Span ~21.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorder with or without congenital anomaliesMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0100465

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to VPS52 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 73

not providedTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_022553.6. 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			2 clinvar		2 clinvar	4
missense			80 clinvar			80
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			11 clinvar			11
Total	0	0	94	0	2	96

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 43 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_022553.6	RefSeq	NP_072047.4	20	MANE Select
ENST00000445902.3	Ensembl	ENSP00000409952.2	20	MANE Select
NM_001289174.2	RefSeq	NP_001276103.1	18	Standard
NM_001289175.1	RefSeq	NP_001276104.1	15	Standard

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

Golgi to vacuole transport
lysosomal transport
ectodermal cell differentiation
protein transport
endocytic recycling

Molecular Function

protein binding
Rab GTPase binding
syntaxin binding

Cellular Component

GARP complex
Golgi apparatus
cytosol
endosome membrane
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000445902
Coding exons: 20
Length: 21776
Individuals with no LoFs: 125708
Homozygous LoFs: 0
Heterozygous LoFs: 40
Defined: 125748
p: 0.000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.50	286	432	0.662	0.0000264	4671
Missense (PolyPhen)		81	139.29	0.58152		1526
Synonymous	1.60	134	160	0.839	0.00000854	1461
Loss of Function	4.30	15	46.7	0.321	0.00000292	461

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00045	0.00043	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.00037	0.00037	rare
European (Non-Finnish)	0.00013	0.00013	rare
South Asian	0.00037	0.00023	rare
Other	0	0.0	absent

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}.;

Intolerance Scores

LoFtool: 0.241
RVIS EVS: -0.51
RVIS percentile EVS: 21.56

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.961

Gene Damage Prediction

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