VPS25

Summary

VPS25 (vacuolar protein sorting 25 homolog, HGNC:28122) is a protein-coding gene on chromosome 17q21.31, encoding Vacuolar protein-sorting-associated protein 25 (Q9BRG1). Component of the ESCRT-II complex (endosomal sorting complex required for transport II), which is required for multivesicular body (MVB) formation and sorting of endosomal cargo proteins into MVBs. It is a common-essential gene (DepMap: required in 99.7% of cancer cell lines).

This gene encodes a protein that is a subunit of the endosomal sorting complex required for transport II (ESCRT-II). This protein complex functions in sorting of ubiquitinated membrane proteins during endocytosis. A pseudogene of this gene is present on chromosome 1.

Source: NCBI Gene 84313 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 20 total — 1 likely-pathogenic
• Cancer dependency (DepMap): dependent in 99.7% of screened cell lines (common-essential)
• MANE Select transcript: NM_032353

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28122
Approved symbol	VPS25
Name	vacuolar protein sorting 25 homolog
Location	17q21.31
Locus type	gene with protein product
Status	Approved
Aliases	MGC10540, EAP20, DERP9
Ensembl gene	ENSG00000131475
Ensembl biotype	protein_coding
OMIM	610907
Entrez	84313

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 6 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000253794, ENST00000589219, ENST00000589520, ENST00000589577, ENST00000590339, ENST00000591584, ENST00000851623, ENST00000934126, ENST00000934127

RefSeq mRNA: 1 — MANE Select: NM_032353 NM_032353

CCDS: CCDS11438

Canonical transcript exons

ENST00000253794 — 6 exons

Exon	Start	End
ENSE00001059264	42778957	42779599
ENSE00001307877	42773449	42773528
ENSE00003465827	42774646	42774699
ENSE00003485719	42775381	42775469
ENSE00003491616	42776245	42776320
ENSE00003616253	42773733	42773878

Expression profiles

Bgee: expression breadth ubiquitous, 249 present calls, max score 96.73.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 63.7078 / max 620.4743, expressed in 1823 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
160991	63.7078	1823

Top tissues by expression

253 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	96.73	gold quality
lower esophagus mucosa	UBERON:0035834	96.33	gold quality
rectum	UBERON:0001052	96.18	gold quality
esophagus mucosa	UBERON:0002469	96.07	gold quality
islet of Langerhans	UBERON:0000006	95.74	gold quality
upper arm skin	UBERON:0004263	95.59	gold quality
right uterine tube	UBERON:0001302	95.35	gold quality
ileal mucosa	UBERON:0000331	95.28	gold quality
metanephros cortex	UBERON:0010533	95.25	gold quality
kidney epithelium	UBERON:0004819	94.52	silver quality
body of stomach	UBERON:0001161	94.39	gold quality
smooth muscle tissue	UBERON:0001135	94.29	gold quality
transverse colon	UBERON:0001157	94.22	gold quality
stromal cell of endometrium	CL:0002255	94.17	gold quality
esophagus	UBERON:0001043	94.17	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.15	gold quality
esophagus squamous epithelium	UBERON:0006920	94.14	gold quality
metanephros	UBERON:0000081	94.06	gold quality
pancreas	UBERON:0001264	94.03	gold quality
monocyte	CL:0000576	93.90	gold quality
right lobe of liver	UBERON:0001114	93.89	gold quality
body of pancreas	UBERON:0001150	93.87	gold quality
leukocyte	CL:0000738	93.83	gold quality
minor salivary gland	UBERON:0001830	93.80	gold quality
adult mammalian kidney	UBERON:0000082	93.75	gold quality
skin of leg	UBERON:0001511	93.73	gold quality
skin of abdomen	UBERON:0001416	93.66	gold quality
mouth mucosa	UBERON:0003729	93.62	gold quality
duodenum	UBERON:0002114	93.59	gold quality
small intestine Peyer’s patch	UBERON:0003454	93.52	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-HCAD-5	no	2.31
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

58 targeting VPS25, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-154-3P	99.50	70.05	831
HSA-MIR-487A-3P	99.50	69.95	840
HSA-MIR-2392	99.43	67.50	708
HSA-MIR-889-3P	99.40	69.76	2103
HSA-MIR-6799-5P	99.14	65.72	2093

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.7% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 2)

• mammalian ESCRTII is made up of hVps25p, hVps22p, and hVps36p and may be redundant, cargo-specific, or not required for protein sorting at the multivesicular body (PMID:16371348)
• Results describe the mapping of multivesicular bodies with the second winged helix domain of human ESCRT-II subunit VPS25 and the first helix of ESCRT-III subunit VPS20. (PMID:19686684)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	vps25	ENSDARG00000059079
mus_musculus	Vps25	ENSMUSG00000078656
rattus_norvegicus	Vps25	ENSRNOG00000078276
drosophila_melanogaster	Vps25	FBGN0022027
caenorhabditis_elegans	vps-25	WBGENE00012193

Protein

Protein identifiers

Vacuolar protein-sorting-associated protein 25 — Q9BRG1 (reviewed: Q9BRG1)

Alternative names: Dermal papilla-derived protein 9, ELL-associated protein of 20 kDa, ESCRT-II complex subunit VPS25

All UniProt accessions (4): Q9BRG1, K7EKV4, K7ENE3, K7EP45

UniProt curated annotations — full annotation on UniProt →

Function. Component of the ESCRT-II complex (endosomal sorting complex required for transport II), which is required for multivesicular body (MVB) formation and sorting of endosomal cargo proteins into MVBs. The MVB pathway mediates delivery of transmembrane proteins into the lumen of the lysosome for degradation. The ESCRT-II complex is probably involved in the recruitment of the ESCRT-III complex. The ESCRT-II complex may also play a role in transcription regulation, possibly via its interaction with ELL. The ESCRT-II complex may be involved in facilitating the budding of certain RNA viruses.

Subunit / interactions. Component of a complex at least composed of ELL, SNF8/EAP30, VPS25/EAP20 and VPS36/EAP45. Component of the endosomal sorting complex required for transport II (ESCRT-II), composed of SNF8, VPS36 and 2 copies of VPS25. Interacts with CFTR; the interaction requires misfolded CFTR. Interacts (via C-terminal half) with the ESCRT-III subunit CHMP6 (via N-terminal half).

Subcellular location. Cytoplasm. Endosome membrane. Nucleus. Nucleoplasm.

Tissue specificity. Expressed at the mRNA level in kidney, liver, pancreas, and placenta. Lower levels of expression are found in heart, skeletal muscle, brain and lung.

Similarity. Belongs to the VPS25 family.

RefSeq proteins (1): NP_115729* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008570	ESCRT-II_cplx_Vps25-sub	Family
IPR014041	ESCRT-II_cplx_Vps25-sub_N	Homologous_superfamily
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily

Pfam: PF05871

UniProt features (24 total): helix 8, strand 7, turn 5, mutagenesis site 2, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3HTU	X-RAY DIFFRACTION	2
3CUQ	X-RAY DIFFRACTION	2.61
2ZME	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BRG1-F1	93.16	0.88

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (2):

Position	Phenotype
124	abolishes binding to chmp6.
126	abolishes binding to chmp6.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-917729	Endosomal Sorting Complex Required For Transport (ESCRT)
R-HSA-9610379	HCMV Late Events

MSigDB gene sets: 178 (showing top): REACTOME_ENDOSOMAL_SORTING_COMPLEX_REQUIRED_FOR_TRANSPORT_ESCRT, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_REGULATION_OF_PROTEIN_TYROSINE_KINASE_ACTIVITY, GOBP_NEGATIVE_REGULATION_OF_PEPTIDYL_TYROSINE_PHOSPHORYLATION, GOBP_REGULATION_OF_ERBB_SIGNALING_PATHWAY, GOBP_ENDOSOME_ORGANIZATION, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_NEGATIVE_REGULATION_OF_KINASE_ACTIVITY, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_VESICLE_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_ERBB_SIGNALING_PATHWAY, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_TYROSINE_KINASE_ACTIVITY, GOBP_VACUOLAR_TRANSPORT, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY

GO Biological Process (7): negative regulation of epidermal growth factor-activated receptor activity (GO:0007175), macroautophagy (GO:0016236), multivesicular body assembly (GO:0036258), protein transport to vacuole involved in ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway (GO:0043328), membrane fission (GO:0090148), protein transport (GO:0015031), multivesicular body sorting pathway (GO:0071985)

GO Molecular Function (3): structural molecule activity (GO:0005198), protein homodimerization activity (GO:0042803), protein binding (GO:0005515)

GO Cellular Component (9): ESCRT II complex (GO:0000814), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), endosome membrane (GO:0010008), extracellular exosome (GO:0070062), endosome (GO:0005768), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Membrane Trafficking	1
HCMV Infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
epidermal growth factor receptor activity	1
negative regulation of epidermal growth factor receptor signaling pathway	1
negative regulation of protein tyrosine kinase activity	1
negative regulation of signaling receptor activity	1
autophagosome assembly	1
autophagy	1
multivesicular body organization	1
organelle assembly	1
intracellular protein transport	1
late endosome to vacuole transport via multivesicular body sorting pathway	1
ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	1
protein localization to vacuole	1
establishment of protein localization to vacuole	1
membrane organization	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
vesicle-mediated transport	1
molecular_function	1
identical protein binding	1
protein dimerization activity	1
binding	1
endosome membrane	1
ESCRT complex	1
membrane protein complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
endosome	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
extracellular vesicle	1
endomembrane system	1
cytoplasmic vesicle	1

Protein interactions and networks

STRING

1259 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VPS25	VPS36	Q86VN1	999
VPS25	CHMP6	Q96FZ7	999
VPS25	SNF8	Q96H20	999
VPS25	CHMP2A	O43633	946
VPS25	CHMP3	Q9Y3E7	933
VPS25	A0A140T963	A0A140T963	930
VPS25	ELL	P55199	927
VPS25	CHMP7	Q8WUX9	919
VPS25	VPS28	Q9UK41	919
VPS25	CHMP5	Q9NZZ3	895
VPS25	CHMP1A	Q9HD42	893
VPS25	TSG101	Q99816	880
VPS25	CHMP4C	Q96CF2	856
VPS25	HGS	O14964	841
VPS25	VPS4A	Q9UN37	841

IntAct

116 interactions, top by confidence:

A	B	Type	Score
SNF8	VPS25	psi-mi:“MI:0915”(physical association)	0.940
VPS25	SNF8	psi-mi:“MI:0915”(physical association)	0.940
VPS25	CHMP6	psi-mi:“MI:0915”(physical association)	0.810
CHMP6	VPS25	psi-mi:“MI:0915”(physical association)	0.810
VPS36	VPS25	psi-mi:“MI:0915”(physical association)	0.800
VPS36	SNF8	psi-mi:“MI:0914”(association)	0.800
VPS25	VPS36	psi-mi:“MI:0914”(association)	0.800
VPS25	TRIM27	psi-mi:“MI:0915”(physical association)	0.780
VPS25	CRLF3	psi-mi:“MI:0915”(physical association)	0.780
TRIM27	VPS25	psi-mi:“MI:0915”(physical association)	0.780
CRLF3	VPS25	psi-mi:“MI:0915”(physical association)	0.780

BioGRID (136): VPS25 (Two-hybrid), VPS25 (Two-hybrid), VPS25 (Two-hybrid), VPS25 (Two-hybrid), VPS25 (Two-hybrid), RHOXF2 (Two-hybrid), VPS25 (Two-hybrid), VPS25 (Two-hybrid), SNF8 (Co-fractionation), VPS25 (Co-fractionation), VPS25 (Two-hybrid), VPS25 (Affinity Capture-MS), VPS25 (Affinity Capture-MS), VPS25 (Affinity Capture-MS), VPS25 (Affinity Capture-MS)

ESM2 similar proteins: A2XKU9, A7RHL5, A9NK39, B4YYA9, B5X8A5, O13907, O42130, O42131, O46374, P0C0A1, P11388, P17248, P23612, P41515, P41516, Q01320, Q02880, Q1JQD4, Q27128, Q498C5, Q498D9, Q4HYB8, Q558Y7, Q5E9A6, Q5E9R3, Q5R4J1, Q5RBP4, Q641Z6, Q64399, Q64511, Q6AVK1, Q6NWF4, Q6P7B0, Q6TGV7, Q6Z9U7, Q7X923, Q8K224, Q8LBN7, Q8T9B6, Q8VZC9

Diamond homologs: O74967, P0C0A1, Q5E9A6, Q6AX45, Q6NWF4, Q7JXV9, Q9BRG1, Q9CQ80, P47142, Q55GD9, Q8VZC9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
VPS25	“form complex”	“ESCRT-II complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 57 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Endosomal Sorting Complex Required For Transport (ESCRT)	5	51.2×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
macroautophagy	5	23.1×	6e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

20 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	13
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2674700	NM_032353.4(VPS25):c.514G>A (p.Gly172Ser)	Likely pathogenic

SpliceAI

808 predictions. Top by Δscore:

Variant	Effect	Δscore
17:42773846:A:T	donor_gain	1.0000
17:42773867:TC:T	donor_gain	1.0000
17:42773872:C:G	donor_gain	1.0000
17:42773877:GC:G	donor_gain	1.0000
17:42775466:GTGG:G	donor_gain	1.0000
17:42776234:T:A	acceptor_gain	1.0000
17:42776237:A:AG	acceptor_gain	1.0000
17:42776241:ACAG:A	acceptor_gain	1.0000
17:42776243:A:AG	acceptor_gain	1.0000
17:42776243:AG:A	acceptor_gain	1.0000
17:42776244:G:GT	acceptor_gain	1.0000
17:42776244:GG:G	acceptor_gain	1.0000
17:42776244:GGT:G	acceptor_gain	1.0000
17:42776244:GGTTT:G	acceptor_gain	1.0000
17:42776314:G:GT	donor_gain	1.0000
17:42776317:GAGG:G	donor_gain	1.0000
17:42776319:GG:G	donor_gain	1.0000
17:42776320:GGTAA:G	donor_gain	1.0000
17:42776321:G:GG	donor_gain	1.0000
17:42776321:G:T	donor_gain	1.0000
17:42778955:A:AG	acceptor_gain	1.0000
17:42778956:G:GG	acceptor_gain	1.0000
17:42778956:GA:G	acceptor_gain	1.0000
17:42773501:GGC:G	donor_gain	0.9900
17:42773529:G:GG	donor_gain	0.9900
17:42773547:G:GT	donor_gain	0.9900
17:42773833:A:AG	donor_gain	0.9900
17:42773836:G:GT	donor_gain	0.9900
17:42773845:G:GT	donor_gain	0.9900
17:42773879:G:GG	donor_gain	0.9900

AlphaMissense

1164 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:42773776:T:A	W33R	0.999
17:42773776:T:C	W33R	0.999
17:42774688:T:C	L81P	0.999
17:42775446:T:A	W107R	0.999
17:42775446:T:C	W107R	0.999
17:42776291:T:C	L130P	0.999
17:42773512:T:C	F13L	0.998
17:42773514:C:A	F13L	0.998
17:42773514:C:G	F13L	0.998
17:42773524:T:C	F17L	0.998
17:42773526:T:A	F17L	0.998
17:42773526:T:G	F17L	0.998
17:42773756:G:C	R26P	0.998
17:42775449:G:T	G108W	0.998
17:42778960:T:C	F141S	0.998
17:42778993:C:A	A152D	0.998
17:42778996:T:C	L153P	0.998
17:42779005:T:C	L156P	0.998
17:42779022:G:C	A162P	0.998
17:42779023:C:A	A162D	0.998
17:42779056:T:A	V173D	0.998
17:42779061:T:C	F175L	0.998
17:42779062:T:C	F175S	0.998
17:42779063:C:A	F175L	0.998
17:42779063:C:G	F175L	0.998
17:42773766:G:C	Q29H	0.997
17:42773766:G:T	Q29H	0.997
17:42773857:T:C	F60L	0.997
17:42773859:C:A	F60L	0.997
17:42773859:C:G	F60L	0.997

dbSNP variants (sampled 300 via entrez): RS1000801135 (17:42773602 T>A,C), RS1001297272 (17:42771730 G>A), RS1001488901 (17:42776778 A>G), RS1001754836 (17:42777764 G>C), RS1002086122 (17:42777024 G>A,T), RS1002128054 (17:42776636 A>G), RS1002212349 (17:42778111 G>C), RS1002309019 (17:42776439 T>C), RS1002692612 (17:42773303 G>A,C), RS1002808861 (17:42779582 T>C), RS1003143428 (17:42773035 A>C), RS1003179229 (17:42772991 T>G), RS1003645525 (17:42773414 C>T), RS1003773170 (17:42771501 C>G), RS1004104473 (17:42771781 C>G,T)

Disease associations

OMIM: gene MIM:610907 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
Endosulfan	decreases expression	2
bisphenol F	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
Atrazine	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Gasoline	affects cotreatment, increases abundance, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, increases abundance, increases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	affects expression	1
Urethane	decreases expression	1
Vincristine	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Cyclosporine	decreases expression	1
Copper Sulfate	decreases expression	1
Lactic Acid	decreases expression	1
1-Butanol	affects cotreatment, increases abundance, increases expression	1
Particulate Matter	affects cotreatment, increases abundance, increases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.