VPS4A

Summary

VPS4A (vacuolar protein sorting 4 homolog A, HGNC:13488) is a protein-coding gene on chromosome 16q23.1, encoding Vacuolar protein sorting-associated protein 4A (Q9UN37). Involved in late steps of the endosomal multivesicular bodies (MVB) pathway. It is a selective cancer dependency (DepMap: 25.7% of cell lines).

The protein encoded by this gene is a member of the AAA protein family (ATPases associated with diverse cellular activities), and is the homolog of the yeast Vps4 protein. In humans, two paralogs of the yeast protein have been identified. The former share a high degree of aa sequence similarity with each other, and also with yeast Vps4 and mouse Skd1 proteins. The mouse Skd1 (suppressor of K+ transport defect 1) has been shown to be really an yeast Vps4 ortholog. Functional studies indicate that both human paralogs associate with the endosomal compartments, and are involved in intracellular protein trafficking, similar to Vps4 protein in yeast. The gene encoding this paralog has been mapped to chromosome 16; the gene for the other resides on chromosome 18.

Source: NCBI Gene 27183 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation syndrome (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 88 total — 4 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 35
• Cancer dependency (DepMap): dependent in 25.7% of screened cell lines
• MANE Select transcript: NM_013245

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13488
Approved symbol	VPS4A
Name	vacuolar protein sorting 4 homolog A
Location	16q23.1
Locus type	gene with protein product
Status	Approved
Aliases	VPS4, VPS4-1, FLJ22197, SKD2, SKD1, SKD1A
Ensembl gene	ENSG00000132612
Ensembl biotype	protein_coding
OMIM	609982
Entrez	27183

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 12 protein_coding, 8 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000254950, ENST00000562754, ENST00000564399, ENST00000566354, ENST00000714472, ENST00000714473, ENST00000714474, ENST00000714475, ENST00000714476, ENST00000714477, ENST00000714478, ENST00000714479, ENST00000714480, ENST00000714481, ENST00000714482, ENST00000714483, ENST00000714484, ENST00000714485, ENST00000714486, ENST00000907004, ENST00000949392, ENST00000949393, ENST00000949394

RefSeq mRNA: 1 — MANE Select: NM_013245 NM_013245

CCDS: CCDS45517

Canonical transcript exons

ENST00000254950 — 11 exons

Exon	Start	End
ENSE00003652237	69316008	69316119
ENSE00004024102	69321051	69321270
ENSE00004024109	69324208	69326939
ENSE00004024112	69311350	69311532
ENSE00004024114	69318650	69318711
ENSE00004024120	69318823	69318942
ENSE00004024122	69320141	69320289
ENSE00004024123	69319387	69319543
ENSE00004024124	69322560	69322700
ENSE00004024125	69316225	69316372
ENSE00004024126	69320688	69320769

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 96.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 98.2413 / max 561.7933, expressed in 1827 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154811	94.7571	1827
154810	3.4842	1612

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	96.03	gold quality
cerebellar vermis	UBERON:0004720	95.72	gold quality
muscle of leg	UBERON:0001383	95.50	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.45	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	95.44	gold quality
parotid gland	UBERON:0001831	95.31	gold quality
apex of heart	UBERON:0002098	95.21	gold quality
cervix squamous epithelium	UBERON:0006922	95.21	gold quality
muscle organ	UBERON:0001630	95.16	gold quality
skeletal muscle organ	UBERON:0014892	95.16	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.12	gold quality
lower esophagus mucosa	UBERON:0035834	95.12	gold quality
middle temporal gyrus	UBERON:0002771	94.96	gold quality
right frontal lobe	UBERON:0002810	94.85	gold quality
endothelial cell	CL:0000115	94.79	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.76	gold quality
skeletal muscle tissue	UBERON:0001134	94.63	gold quality
cerebellar hemisphere	UBERON:0002245	94.57	gold quality
cerebellar cortex	UBERON:0002129	94.56	gold quality
primary visual cortex	UBERON:0002436	94.42	gold quality
triceps brachii	UBERON:0001509	94.41	gold quality
cerebellum	UBERON:0002037	94.32	gold quality
body of pancreas	UBERON:0001150	94.22	gold quality
inferior olivary complex	UBERON:0002127	94.22	gold quality
quadriceps femoris	UBERON:0001377	94.21	gold quality
gluteal muscle	UBERON:0002000	94.19	gold quality
vastus lateralis	UBERON:0001379	94.10	gold quality
putamen	UBERON:0001874	94.10	gold quality
cingulate cortex	UBERON:0003027	94.09	gold quality
anterior cingulate cortex	UBERON:0009835	94.08	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.84

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F4

miRNA regulators (miRDB)

56 targeting VPS4A, 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-3120-5P	100.00	65.56	965
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-7515	99.31	68.22	1795
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-3064-5P	99.26	66.13	1497
HSA-MIR-3085-3P	99.26	66.16	1490
HSA-MIR-6504-5P	99.26	65.95	1487
HSA-MIR-149-5P	99.25	67.16	1315
HSA-MIR-593-3P	99.22	67.28	1327

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 25.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• SKD1-dependent endosomal membrane trafficking is required for formation of autolysosomes. (PMID:11937716)
• CHMP4b and Alix participate in formation of multivesicular bodies by cooperating with SKD1 (PMID:12860994)
• Data suggested that hVPS4 is involved in the release of components of the bilayered coat from the endosomal membrane. (PMID:15075231)
• hSnf7-1 binds to itself, membranes, and the AAA+ ATPase SKD1 (PMID:15632132)
• The solution structure of the N-terminal VPS4A microtubule interacting and transport (MIT) domain was reported. (PMID:16174732)
• in cells expressing dominant negative VPS4a, doxorubicin accumulates in VPS4a-positive vesicles and drug sequestration is inhibited (PMID:16841193)
• Upon coexpression of mutated CHMP3, CHMP4B, or CHMP4C forms, as well as of ATPase-defective Vps4A or Vps4B mutants, HBV assembly and egress were potently blocked. (PMID:17553870)
• Here, we report that dominant negative forms of Vps4A, Vps4B, and AIP1 inhibit HTLV-1 budding. (PMID:17601348)
• Inhibits Vesicular Stomatitis Virus budding but does not affect Semliki Forest Virus budding. (PMID:17913808)
• studies reveal how the VPS4 ATPases recognize their CHMP substrates to facilitate the membrane fission events required for the release of viruses, endosomal vesicles and daughter cells (PMID:17928862)
• Respiratory syncytial virus uses a Vps4-independent budding mechanism controlled by Rab11-FIP2. (PMID:18621683)
• Overall, we see no role for the ESCRT pathway in influenza virus budding and the significance of the M1-VPS28 interaction remains to be determined. (PMID:19524996)
• Both Vps4A and CHMP1A localized in the vicinity of viral cytoplasmic assembly compartments, sites of viral maturation that develop in Cytomegalovirus-infected cells. Thus, ESCRT machinery is involved in the final steps of HCMV replication. (PMID:19640981)
• Vps4 and the ESCRT-III complex are required for the release of infectious hepatitis C virus particles. (PMID:19828764)
• A common substrate recognition mode conserved between katanin p60 and VPS4 governs microtubule severing and membrane skeleton reorganization (PMID:20339000)
• ESCRT-III/VPS4 proteins function at centrosomes to help regulate their maintenance or proliferation and then at midbodies during abscission, thereby helping ensure the ordered progression through the different stages of cell division. (PMID:20616062)
• It was found that neither siRNA knockdown of VPS4A and VPS4B expression nor the use of cell lines that inducibly express VPS4A or VPS4B dominant negative mutants, inhibited influenza virus budding. (PMID:20621136)
• Findings reveal new ways in which VPS4 activity is regulated and specifically directed to ESCRT-III polymers. (PMID:20805225)
• These results indicate that VPS4A has a direct role in membrane scission leading to HIV-1 release. (PMID:21394086)
• VPS4, a master regulator of MVB sorting, may serve as a determinant of lysosomal targeting or extracellular secretion of alphaSYN and thereby contribute to the intercellular propagation of Lewy pathology in PD (PMID:22216284)
• silencing CHMP6 and VPS4A also blocked epidermal growth factor receptor (EGFR) recycling (PMID:22231449)
• VPS4 is required for endosomal transport of LDL cholesterol in HeLa cells. (PMID:23009658)
• Propose that the abscission checkpoint is mediated by ANCHR and CHMP4C through retention of VPS4 at the midbody ring. (PMID:24814515)
• these experiments suggest that miR-16 and VPS4a expression are altered in end-stage heart failure and in response to unloading with a left ventricular assist device (PMID:25033200)
• Vps4 stimulatory element of the cofactor Vta1 contacts the ATPase Vps4 alpha7 and alpha9 subunits to stimulate ATP hydrolysis. (PMID:25164817)
• Vps4A may function as a tumor suppressor, which utilizes exosomes as mediators to regulate the secretion and uptake of miRNAs in hepatoma cells; these observations provide new insights into the development of HCC. (PMID:25503676)
• Ca2+-dependent accumulation of ESCRT III-Vps4 complex following large focal injury to the cell membrane and identify the role of ALG-2 as the initiator of sequential ESCRT III-Vps4A/B complex assembly. (PMID:25534348)
• These results point to the existence of previously undetected biological functions of the FTase alpha subunit that includes control of intracellular membrane trafficking. (PMID:26551458)
• associations were noted between the striatal node, hyperactivity, and the vacuolar protein sorting-associated protein 4A (VPS4A) gene in humans, and the causal role of Vps4 for hyperactivity was validated in Drosophila (PMID:27001827)
• These results demonstrate that the ESCRT machinery, and in particular VPS4, plays a critical role in the early stages of PV infection. (PMID:28349933)
• Continuous ESCRT-III remodelling by dynamic subunit turnover is regulated by Vps4 to mediate membrane remodelling during cytokinesis. (PMID:28604678)
• Visualization of IST1 structures in cells lacking the microtubule-severing enzyme spastin and in cells depleted of specific ESCRT-III components or the ATPase VPS4 demonstrated the contribution of these components to the organization and function of ESCRTs in cells. (PMID:30110633)
• Vps4A regulates the plasma membrane localization and exosome sorting of beta-catenin, consequently decreasing beta-catenin signaling, and thereby inhibiting epithelial mesenchymal transformation and metastasis in hepatocellular carcinoma. (PMID:31059752)
• Synthetic lethality between VPS4A and VPS4B triggers an inflammatory response in colorectal cancer. (PMID:31930723)
• VPS4A Mutations in Humans Cause Syndromic Congenital Dyserythropoietic Anemia due to Cytokinesis and Trafficking Defects. (PMID:33186543)
• De Novo VPS4A Mutations Cause Multisystem Disease with Abnormal Neurodevelopment. (PMID:33186545)
• Synthetic Lethal Interaction between the ESCRT Paralog Enzymes VPS4A and VPS4B in Cancers Harboring Loss of Chromosome 18q or 16q. (PMID:33326793)
• VPS4A mutation in syndromic congenital hemolytic anemia without obvious signs of dyserythropoiesis. (PMID:33460484)
• Vaccinia virus hijacks ESCRT-mediated multivesicular body formation for virus egress. (PMID:34145027)
• The ESCRT-III protein VPS4, but not CHMP4B or CHMP2B, is pathologically increased in familial and sporadic ALS neuronal nuclei. (PMID:34281622)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	vps4a	ENSDARG00000030114
mus_musculus	Vps4a	ENSMUSG00000031913
rattus_norvegicus	Vps4a	ENSRNOG00000020351
drosophila_melanogaster	Fign	FBGN0031519
drosophila_melanogaster	kat-60L1	FBGN0037375
drosophila_melanogaster	Kat60	FBGN0040208
caenorhabditis_elegans	mei-1	WBGENE00003183
caenorhabditis_elegans		WBGENE00017981

Paralogs (9): SPAST (ENSG00000021574), KATNAL1 (ENSG00000102781), VPS4B (ENSG00000119541), FIGNL1 (ENSG00000132436), ATAD1 (ENSG00000138138), KATNAL2 (ENSG00000167216), FIGN (ENSG00000182263), KATNA1 (ENSG00000186625), FIGNL2 (ENSG00000261308)

Protein

Protein identifiers

Vacuolar protein sorting-associated protein 4A — Q9UN37 (reviewed: Q9UN37)

Alternative names: Protein SKD2, VPS4-1

All UniProt accessions (13): Q9UN37, A0AAQ5BI04, A0AAQ5BI05, A0AAQ5BI14, A0AAQ5BI15, A0AAQ5BI17, A0AAQ5BI29, A0AAQ5BI38, A0AAQ5BI50, A0AAQ5BI51, A0AAQ5BI54, A0AAQ5BI57, A0AAQ5BI89

UniProt curated annotations — full annotation on UniProt →

Function. Involved in late steps of the endosomal multivesicular bodies (MVB) pathway. Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly, possibly in combination with membrane fission. Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. It is required for proper accomplishment of various processes including the regulation of endosome size, primary cilium organization, mitotic spindle organization, chromosome segregation, and nuclear envelope sealing and spindle disassembly during anaphase. Involved in cytokinesis: retained at the midbody by ZFYVE19/ANCHR and CHMP4C until abscission checkpoint signaling is terminated at late cytokinesis. It is then released following dephosphorylation of CHMP4C, leading to abscission. VPS4A/B are required for the exosomal release of SDCBP, CD63 and syndecan. Critical for normal erythroblast cytokinesis and correct erythropoiesis. (Microbial infection) In conjunction with the ESCRT machinery also appears to function in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis and enveloped virus budding (HIV-1 and other lentiviruses).

Subunit / interactions. Proposed to be monomeric or homodimeric in nucleotide-free form and to oligomerize upon binding to ATP to form two stacked hexameric or heptameric rings with a central pore through which ESCRT-III substrates are translocated in an ATP-dependent manner. Interacts with CHMP1A, CHMP1B, CHMP2A, CHMP2B, CHMP3, CHMP4A, CHMP4B, CHMP4C and CHMP6. Interacts with VPS4B; the interaction suggests a heteromeric assembly with VPS4B. Interacts with SPAST. Interacts with IST1. Interacts with ZFYVE19/ANCHR; leading to retain it at midbody.

Subcellular location. Late endosome membrane. Midbody. Cytoplasm. Cytoskeleton. Spindle.

Tissue specificity. Ubiquitously expressed.

Disease relevance. CIMDAG syndrome (CIMDAG) [MIM:619273] An autosomal dominant syndrome characterized by global developmental delay, severely impaired intellectual development, poor or absent speech, microcephaly, growth retardation, poor motor skills with inability to walk, hypotonia and spasticity, and cataracts. Cerebral and cerebellar atrophy, thin corpus callosum, and delayed myelination are apparent on brain imaging. Affected individuals show hematologic abnormalities mostly consistent with congenital dyserythropoietic anemia. The disease may be caused by variants affecting the gene represented in this entry.

Domain organisation. The MIT domain serves as an adapter for ESCRT-III proteins. It forms an asymmetric three-helix bundle that binds amphipathic MIM (MIT interacting motif) helices along the groove between MIT helices 2 and 3 present in a subset of ESCRT-III proteins thus establishing the canonical MIM-MIT interaction. In an extended conformation along the groove between helices 1 and 3, also binds to a type-2 MIT interacting motif (MIM2).

Similarity. Belongs to the AAA ATPase family.

RefSeq proteins (1): NP_037377* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003593	AAA+_ATPase	Domain
IPR003959	ATPase_AAA_core	Domain
IPR003960	ATPase_AAA_CS	Conserved_site
IPR007330	MIT_dom	Domain
IPR015415	Spast_Vps4_C	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036181	MIT_dom_sf	Homologous_superfamily
IPR041569	AAA_lid_3	Domain
IPR045253	VPS4_MIT	Domain
IPR050304	MT-severing_AAA_ATPase	Family

Pfam: PF00004, PF04212, PF09336, PF17862

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (34 total): mutagenesis site 11, sequence variant 8, sequence conflict 3, helix 3, modified residue 3, region of interest 2, chain 1, domain 1, compositionally biased region 1, binding site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
1YXR	SOLUTION NMR
2JQ9	SOLUTION NMR
2K3W	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UN37-F1	85.94	0.58

Functional residue map

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

Ligand- & substrate-binding residues (1): 167–174

Post-translational modifications (3): 8, 95, 97

Mutagenesis-validated functional residues (11):

Position	Phenotype
13	diminishes interaction with ist1.
13	abolishes interaction with chmp6, no effect on interaction with chmp1a.
13	greatly diminishes localization to punctate class e compartments; when associated with q-173.
64	abolishes interaction with chmp1b; diminishes interaction with ist1.
64	greatly diminishes localization to punctate class e compartments and partially restores hiv-1 release; when associated w
64	modestly reduces interaction with chmp6.
68	diminishes interaction with chmp1b.
173	defective in atp-binding. causes membrane association. induces vacuolation of endosomal compartments and impairs cholest
201–202	strongly impairs hiv-1 release.
203	impairs hiv-1 release.
228	defective in atp-hydrolysis. causes membrane association. induces vacuolation of endosomal compartments and impairs chol

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-162588	Budding and maturation of HIV virion
R-HSA-917729	Endosomal Sorting Complex Required For Transport (ESCRT)
R-HSA-9610379	HCMV Late Events
R-HSA-9668328	Sealing of the nuclear envelope (NE) by ESCRT-III

MSigDB gene sets: 341 (showing top): GOBP_MITOTIC_CYTOKINESIS, REACTOME_ENDOSOMAL_SORTING_COMPLEX_REQUIRED_FOR_TRANSPORT_ESCRT, GOBP_CHROMOSOME_ORGANIZATION, GOBP_NUCLEAR_MEMBRANE_REASSEMBLY, GOBP_LYSOSOMAL_TRANSPORT, chr16q22, GOBP_ENDOSOME_ORGANIZATION, GOBP_VACUOLE_ORGANIZATION, GOBP_VESICLE_LOCALIZATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_CELL_DIVISION, GOBP_MEMBRANE_BIOGENESIS, GOCC_VACUOLAR_MEMBRANE, GOBP_VESICLE_ORGANIZATION, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN

GO Biological Process (46): actomyosin contractile ring contraction (GO:0000916), plasma membrane repair (GO:0001778), protein targeting to lysosome (GO:0006622), vesicle budding from membrane (GO:0006900), autophagy (GO:0006914), nucleus organization (GO:0006997), nuclear envelope organization (GO:0006998), vacuole organization (GO:0007033), mitotic metaphase chromosome alignment (GO:0007080), mitotic nuclear membrane reassembly (GO:0007084), vesicle-mediated transport (GO:0016192), endosomal transport (GO:0016197), macroautophagy (GO:0016236), viral release from host cell (GO:0019076), nuclear membrane reassembly (GO:0031468), intracellular cholesterol transport (GO:0032367), negative regulation of cytokinesis (GO:0032466), regulation of protein localization (GO:0032880), endosomal vesicle fusion (GO:0034058), multivesicular body assembly (GO:0036258), viral budding via host ESCRT complex (GO:0039702), ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway (GO:0043162), mitotic cytokinesis checkpoint signaling (GO:0044878), viral budding from plasma membrane (GO:0046761), cell division (GO:0051301), cytoskeleton-dependent cytokinesis (GO:0061640), late endosomal microautophagy (GO:0061738), late endosome to lysosome transport via multivesicular body sorting pathway (GO:0061764), midbody abscission (GO:0061952), multivesicular body sorting pathway (GO:0071985), vesicle uncoating (GO:0072319), membrane fission (GO:0090148), obsolete ubiquitin-independent protein catabolic process via the multivesicular body sorting pathway (GO:0090611), autophagosome maturation (GO:0097352), regulation of protein localization to plasma membrane (GO:1903076), positive regulation of exosomal secretion (GO:1903543), positive regulation of viral budding via host ESCRT complex (GO:1903774), ESCRT complex disassembly (GO:1904896), ESCRT III complex disassembly (GO:1904903), endosome organization (GO:0007032)

GO Molecular Function (7): ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), protein-containing complex binding (GO:0044877), ATP-dependent protein disaggregase activity (GO:0140545), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (23): spindle pole (GO:0000922), nucleus (GO:0005634), nuclear pore (GO:0005643), cytoplasm (GO:0005737), lysosome (GO:0005764), endosome (GO:0005768), early endosome (GO:0005769), late endosome (GO:0005770), vacuolar membrane (GO:0005774), centrosome (GO:0005813), cytosol (GO:0005829), plasma membrane (GO:0005886), endosome membrane (GO:0010008), midbody (GO:0030496), late endosome membrane (GO:0031902), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), Flemming body (GO:0090543), ATPase complex (GO:1904949), spindle (GO:0005819), cytoskeleton (GO:0005856), endomembrane system (GO:0012505), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Late Phase of HIV Life Cycle	1
Membrane Trafficking	1
HCMV Infection	1
Nuclear Envelope (NE) Reassembly	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
endosome	3
vesicle-mediated transport	2
membrane organization	2
organelle organization	2
mitotic cell cycle	2
intracellular anatomical structure	2
ATP-dependent activity	2
binding	2
bounding membrane of organelle	2
cytoplasm	2
contractile ring contraction	1
actomyosin contractile ring organization	1
plasma membrane organization	1
wound healing	1
protein targeting to vacuole	1
lysosomal transport	1
protein localization to lysosome	1
vesicle organization	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
nucleus organization	1
endomembrane system organization	1
mitotic sister chromatid segregation	1
metaphase chromosome alignment	1
mitotic cell cycle process	1
nuclear membrane reassembly	1
mitotic nuclear membrane organization	1
transport	1
cellular process	1
intracellular transport	1
autophagosome assembly	1
autophagy	1
viral process	1
viral life cycle	1
exit from host cell	1
membrane assembly	1
nuclear membrane organization	1
cholesterol transport	1

Protein interactions and networks

STRING

1543 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VPS4A	VTA1	Q9NP79	994
VPS4A	CHMP1A	Q9HD42	975
VPS4A	CHMP5	Q9NZZ3	970
VPS4A	CHMP2A	O43633	964
VPS4A	CHMP6	Q96FZ7	955
VPS4A	CHMP2B	Q9UQN3	955
VPS4A	A0A140T963	A0A140T963	950
VPS4A	CHMP3	Q9Y3E7	949
VPS4A	CHMP1B	Q7LBR1	947
VPS4A	VPS28	Q9UK41	942
VPS4A	CHMP4A	Q9BY43	937
VPS4A	TSG101	Q99816	920
VPS4A	VPS37B	Q9H9H4	912
VPS4A	PDCD6IP	Q8WUM4	855
VPS4A	CHMP4C	Q96CF2	850

IntAct

99 interactions, top by confidence:

A	B	Type	Score
VPS4A	CFTR	psi-mi:“MI:0915”(physical association)	0.790
CFTR	VPS4A	psi-mi:“MI:0915”(physical association)	0.790
CFTR	XPO1	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CHMP1A	VPS4A	psi-mi:“MI:0915”(physical association)	0.660
VPS4A	CHMP1A	psi-mi:“MI:0915”(physical association)	0.660
VPS4A	CHMP1B	psi-mi:“MI:0915”(physical association)	0.590
CHMP1B	VPS4A	psi-mi:“MI:0915”(physical association)	0.590
CHMP1B	VPS4A	psi-mi:“MI:0407”(direct interaction)	0.590
CHMP1A	VPS4A	psi-mi:“MI:0407”(direct interaction)	0.560
CLIC3	VPS4A	psi-mi:“MI:0915”(physical association)	0.560
CHMP2A	VPS4A	psi-mi:“MI:0915”(physical association)	0.550
VPS4A	CHMP2A	psi-mi:“MI:0914”(association)	0.550
VPS4A	VPS4B	psi-mi:“MI:0914”(association)	0.530
VPS4A	IST1	psi-mi:“MI:0914”(association)	0.530
CFTR	CNOT1	psi-mi:“MI:0914”(association)	0.480
VPS4A	CHMP2B	psi-mi:“MI:0407”(direct interaction)	0.440
CHMP3	VPS4A	psi-mi:“MI:0915”(physical association)	0.400
ZFYVE19	VPS4A	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (133): ATP1A3 (Affinity Capture-MS), VPS4B (Affinity Capture-MS), RHEB (Affinity Capture-MS), ZFYVE19 (Affinity Capture-MS), VTA1 (Affinity Capture-MS), ARL8B (Affinity Capture-MS), VPS4A (Co-fractionation), VPS4A (Affinity Capture-MS), VPS4A (Affinity Capture-MS), VPS4A (Affinity Capture-MS), VPS4A (Affinity Capture-MS), VPS4A (Affinity Capture-MS), VPS4A (Affinity Capture-MS), VPS4A (Affinity Capture-MS), VPS4A (Affinity Capture-MS)

ESM2 similar proteins: B4F6J6, D0FH76, F6QV99, O75351, P03974, P18708, P23787, P28737, P46459, P46460, P46461, P46462, P46467, P52917, P54351, P54609, P54774, P54811, P54812, P54815, P55072, Q01853, Q09803, Q0DGP6, Q0VD48, Q3ZBT1, Q503W7, Q505J9, Q54PT2, Q5AG40, Q5R410, Q5R658, Q6GL04, Q75JI3, Q793F9, Q7KN62, Q7ZU99, Q7ZZ25, Q8NBU5, Q8VEJ9

Diamond homologs: A0A8I6AGW3, A0LR74, A2VDN5, A4IHT0, A6NMB9, B2RYN7, B3M301, B3P8A3, B4F6J6, B4G437, B4HGG6, B4JII0, B4K799, B4M0H8, B4NBP4, B4PL32, B4QSF0, B7PXE3, D0FH76, D2VS83, E9QEA3, F4JEX5, F6QV99, J3QK54, O05209, O14114, O14325, O15381, O16299, O28972, O57940, O60058, P03974, P23787, P25694, P32794, P36966, P40340, P46462, P54609

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
VPS4A	“up-regulates activity”	CHMP2A	cleavage
VPS4A	“up-regulates activity”	CHMP3	cleavage

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 88 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
Budding and maturation of HIV virion	9	61.2×	5e-12
Sealing of the nuclear envelope (NE) by ESCRT-III	9	51.9×	1e-11
Endosomal Sorting Complex Required For Transport (ESCRT)	8	49.1×	4e-10
Late endosomal microautophagy	8	43.5×	9e-10
Pyroptosis	6	42.3×	3e-07
Macroautophagy	9	17.3×	1e-07
HCMV Late Events	8	13.1×	7e-06
PKR-mediated signaling	5	11.8×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
nuclear membrane reassembly	9	114.4×	2e-15
viral budding via host ESCRT complex	11	113.2×	1e-18
midbody abscission	12	112.7×	4e-20
late endosome to lysosome transport	8	101.7×	2e-13
regulation of centrosome duplication	10	93.9×	4e-16
multivesicular body sorting pathway	9	92.6×	1e-14
regulation of mitotic spindle assembly	9	84.5×	3e-14
multivesicular body assembly	12	81.0×	2e-18

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	1
Uncertain significance	61
Likely benign	9
Benign	2

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
976850	NM_013245.3(VPS4A):c.850A>T (p.Arg284Trp)	Pathogenic
976851	NM_013245.3(VPS4A):c.850A>G (p.Arg284Gly)	Pathogenic
976852	NM_013245.3(VPS4A):c.616G>A (p.Glu206Lys)	Pathogenic
996555	NM_013245.3(VPS4A):c.608G>A (p.Gly203Glu)	Pathogenic
3368966	NM_013245.3(VPS4A):c.346G>A (p.Ala116Thr)	Likely pathogenic

SpliceAI

2261 predictions. Top by Δscore:

Variant	Effect	Δscore
16:69311528:TCCAG:T	donor_loss	1.0000
16:69311529:CCAG:C	donor_loss	1.0000
16:69311530:CAGGT:C	donor_loss	1.0000
16:69311531:AG:A	donor_loss	1.0000
16:69311532:GGTAC:G	donor_loss	1.0000
16:69311533:G:GA	donor_loss	1.0000
16:69311534:T:G	donor_loss	1.0000
16:69316004:CCA:C	acceptor_loss	1.0000
16:69316006:A:AG	acceptor_gain	1.0000
16:69316006:A:T	acceptor_loss	1.0000
16:69316007:G:GA	acceptor_gain	1.0000
16:69316007:G:GG	acceptor_gain	1.0000
16:69316007:G:T	acceptor_loss	1.0000
16:69316007:GA:G	acceptor_gain	1.0000
16:69316007:GAA:G	acceptor_gain	1.0000
16:69316007:GAAA:G	acceptor_gain	1.0000
16:69316116:AAGT:A	donor_gain	1.0000
16:69316117:AGTGT:A	donor_loss	1.0000
16:69316118:GT:G	donor_gain	1.0000
16:69316119:TG:T	donor_loss	1.0000
16:69316120:G:GG	donor_gain	1.0000
16:69316120:GTGA:G	donor_loss	1.0000
16:69316221:A:AG	acceptor_gain	1.0000
16:69316221:ACAG:A	acceptor_loss	1.0000
16:69316222:C:G	acceptor_gain	1.0000
16:69316222:CA:C	acceptor_loss	1.0000
16:69316223:A:AG	acceptor_gain	1.0000
16:69316223:A:C	acceptor_loss	1.0000
16:69316223:AGAT:A	acceptor_gain	1.0000
16:69316223:AGATG:A	acceptor_gain	1.0000

AlphaMissense

2885 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:69316288:G:C	R66P	1.000
16:69316290:G:C	A67P	1.000
16:69318855:T:A	W126R	1.000
16:69318855:T:C	W126R	1.000
16:69318857:G:C	W126C	1.000
16:69318857:G:T	W126C	1.000
16:69318895:T:A	L139H	1.000
16:69318895:T:C	L139P	1.000
16:69318903:G:C	A142P	1.000
16:69318936:T:C	F153L	1.000
16:69318938:C:A	F153L	1.000
16:69318938:C:G	F153L	1.000
16:69319414:T:C	L164P	1.000
16:69319417:T:C	L165P	1.000
16:69319422:G:A	G167R	1.000
16:69319422:G:C	G167R	1.000
16:69319423:G:A	G167E	1.000
16:69319431:G:C	G170R	1.000
16:69319432:G:A	G170D	1.000
16:69319437:G:A	G172R	1.000
16:69319437:G:C	G172R	1.000
16:69319437:G:T	G172W	1.000
16:69319438:G:A	G172E	1.000
16:69319438:G:T	G172V	1.000
16:69319440:A:C	K173Q	1.000
16:69319441:A:T	K173I	1.000
16:69319450:T:C	L176P	1.000
16:69319453:C:A	A177D	1.000
16:69319458:G:C	A179P	1.000
16:69319459:C:A	A179D	1.000

dbSNP variants (sampled 300 via entrez): RS1000066493 (16:69314034 C>A,T), RS1000152283 (16:69324406 T>A), RS1000159915 (16:69326488 T>G), RS1000410487 (16:69312370 A>G,T), RS1000414191 (16:69324143 T>C), RS1000509253 (16:69316492 A>C,G), RS1000558064 (16:69317453 T>C), RS1000646350 (16:69310797 C>T), RS1001015307 (16:69310418 C>A,G), RS1001035086 (16:69317608 A>C), RS1001073235 (16:69320490 T>C), RS1001116254 (16:69313186 T>G), RS1001189897 (16:69313556 C>T), RS1001567094 (16:69321012 C>T), RS1001700872 (16:69324646 C>G)

Disease associations

OMIM: gene MIM:609982 | disease phenotypes: MIM:619273

GenCC curated gene-disease

Disease	Classification	Inheritance
cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation syndrome	Definitive	Autosomal dominant
intellectual disability	Limited	Autosomal dominant

Mondo (2): cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation syndrome (MONDO:0035819), intellectual disability (MONDO:0001071)

Orphanet (1): Cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation syndrome (Orphanet:603448)

HPO phenotypes

35 total (30 of 35 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000135	Hypogonadism
HP:0000252	Microcephaly
HP:0000407	Sensorineural hearing impairment
HP:0000505	Visual impairment
HP:0000519	Developmental cataract
HP:0000556	Retinal dystrophy
HP:0000750	Delayed speech and language development
HP:0001081	Cholelithiasis
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001270	Motor delay
HP:0001320	Cerebellar vermis hypoplasia
HP:0001321	Cerebellar hypoplasia
HP:0001332	Dystonia
HP:0001344	Absent speech
HP:0001414	Microvesicular hepatic steatosis
HP:0002059	Cerebral atrophy
HP:0002072	Chorea
HP:0002126	Polymicrogyria
HP:0002240	Hepatomegaly
HP:0002360	Sleep disturbance
HP:0002719	Recurrent infections
HP:0006879	Pontocerebellar atrophy
HP:0009125	Lipodystrophy
HP:0010864	Severe intellectual disability
HP:0011344	Severe global developmental delay
HP:0011451	Primary microcephaly

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST005446_34	Total cholesterol levels in HDL	2.000000e-08
GCST005951_13	Body mass index	5.000000e-11
GCST006611_17	HDL cholesterol	3.000000e-10
GCST007006_16	Logical memory (delayed recall) in normal cognition	7.000000e-07
GCST010703_183	Brain morphology (MOSTest)	5.000000e-11

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004340	body mass index
EFO:0004874	memory performance
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

38 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases methylation, affects cotreatment, increases methylation	2
Tobacco Smoke Pollution	affects expression, increases expression	2
FR900359	increases phosphorylation	1
dicrotophos	increases expression	1
decabromobiphenyl ether	decreases expression	1
beta-lapachone	decreases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
tetrabromobisphenol A	decreases expression	1
manganese chloride	decreases expression, increases abundance	1
benzo(e)pyrene	decreases methylation	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	decreases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol S	decreases methylation	1
LDN 193189	affects cotreatment, increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Irinotecan	decreases expression	1
Temozolomide	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Aspirin	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Dactinomycin	affects cotreatment, increases secretion	1
Doxorubicin	decreases expression	1
Ivermectin	decreases expression	1
Manganese	decreases expression, increases abundance	1

Cellosaurus cell lines

8 cell lines: 8 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_TX59	HAP1 VPS4A (-) 1	Cancer cell line	Male
CVCL_TX60	HAP1 VPS4A (-) 2	Cancer cell line	Male
CVCL_TX61	HAP1 VPS4A (-) 3	Cancer cell line	Male
CVCL_TX62	HAP1 VPS4A (-) 4	Cancer cell line	Male
CVCL_TX63	HAP1 VPS4A (-) 5	Cancer cell line	Male
CVCL_TX64	HAP1 VPS4A (-) 6	Cancer cell line	Male
CVCL_TX65	HAP1 VPS4A (-) 7	Cancer cell line	Male
CVCL_TX66	HAP1 VPS4A (-) 8	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders