VDAC2

Summary

VDAC2 (voltage dependent anion channel 2, HGNC:12672) is a protein-coding gene on chromosome 10q22.2, encoding Non-selective voltage-gated ion channel VDAC2 (P45880). Non-selective voltage-gated ion channel that mediates the transport of anions and cations through the mitochondrion outer membrane and plasma membrane.

This gene encodes a member of the voltage-dependent anion channel pore-forming family of proteins that are considered the main pathway for metabolite diffusion across the mitochondrial outer membrane. The encoded protein is also thought to be involved in the mitochondrial apoptotic pathway via regulation of BCL2-antagonist/killer 1 protein activity. Pseudogenes have been identified on chromosomes 1, 2, 12 and 21, and alternative splicing results in multiple transcript variants.

Source: NCBI Gene 7417 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 46 total
• Phenotypes (HPO): 1
• Druggable target: yes
• MANE Select transcript: NM_001391963

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12672
Approved symbol	VDAC2
Name	voltage dependent anion channel 2
Location	10q22.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000165637
Ensembl biotype	protein_coding
OMIM	193245
Entrez	7417

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 19 protein_coding, 4 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000298468, ENST00000313132, ENST00000332211, ENST00000344036, ENST00000413289, ENST00000447677, ENST00000460044, ENST00000468285, ENST00000470745, ENST00000472137, ENST00000475142, ENST00000481876, ENST00000498394, ENST00000543351, ENST00000880919, ENST00000880920, ENST00000880921, ENST00000880922, ENST00000880923, ENST00000880924, ENST00000880925, ENST00000880926, ENST00000933154, ENST00000958957, ENST00000958958, ENST00000958959

RefSeq mRNA: 8 — MANE Select: NM_001391963 NM_001184783, NM_001184823, NM_001324087, NM_001324088, NM_001324089, NM_001324090, NM_001391963, NM_003375

CCDS: CCDS53544, CCDS7348

Canonical transcript exons

ENST00000332211 — 10 exons

Exon	Start	End
ENSE00001166933	75229644	75229701
ENSE00001166940	75222252	75222402
ENSE00001458201	75230898	75231448
ENSE00001897839	75210796	75210938
ENSE00003509458	75214021	75214070
ENSE00003562106	75219304	75219356
ENSE00003565605	75211134	75211189
ENSE00003590294	75212230	75212298
ENSE00003598568	75219063	75219215
ENSE00003785968	75220743	75220970

Expression profiles

Bgee: expression breadth ubiquitous, 161 present calls, max score 99.19.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 90.2495 / max 740.4391, expressed in 1825 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
105618	86.2610	1825
105619	2.0636	1266
105616	1.0154	693
105617	0.8859	591
105615	0.0236	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
esophagus mucosa	UBERON:0002469	99.19	gold quality
gastrocnemius	UBERON:0001388	99.18	gold quality
heart left ventricle	UBERON:0002084	99.13	gold quality
muscle of leg	UBERON:0001383	99.11	gold quality
skeletal muscle organ	UBERON:0014892	99.06	gold quality
esophagus	UBERON:0001043	99.04	gold quality
embryo	UBERON:0000922	99.01	gold quality
ganglionic eminence	UBERON:0004023	99.01	gold quality
cortical plate	UBERON:0005343	99.01	gold quality
heart	UBERON:0000948	99.00	gold quality
right atrium auricular region	UBERON:0006631	98.99	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.93	gold quality
apex of heart	UBERON:0002098	98.92	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.92	gold quality
rectum	UBERON:0001052	98.91	gold quality
sigmoid colon	UBERON:0001159	98.90	gold quality
vagina	UBERON:0000996	98.88	gold quality
smooth muscle tissue	UBERON:0001135	98.87	gold quality
lower esophagus	UBERON:0013473	98.87	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.87	gold quality
lower esophagus mucosa	UBERON:0035834	98.86	gold quality
mucosa of transverse colon	UBERON:0004991	98.85	gold quality
islet of Langerhans	UBERON:0000006	98.84	gold quality
body of pancreas	UBERON:0001150	98.80	gold quality
transverse colon	UBERON:0001157	98.80	gold quality
skin of abdomen	UBERON:0001416	98.76	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.75	gold quality
skeletal muscle tissue	UBERON:0001134	98.74	gold quality
colon	UBERON:0001155	98.74	gold quality
zone of skin	UBERON:0000014	98.71	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	225.54
E-CURD-112	yes	17.29
E-MTAB-10042	yes	9.31
E-GEOD-100618	no	1040.10
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

60 targeting VDAC2, 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-5692A	100.00	74.40	6850
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-132-3P	99.73	70.56	1424
HSA-MIR-212-3P	99.73	70.65	1424
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-6758-3P	99.57	67.55	1078
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-4753-5P	99.54	68.51	1356
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-8064	99.45	66.92	875
HSA-MIR-889-5P	99.41	68.75	1025
HSA-MIR-133A-5P	99.28	69.13	941

Literature-anchored findings (GeneRIF, showing 40)

• TAB2 is a functionally conserved component of the tumor necrosis factor/Eiger signaling pathway. (PMID:16079232)
• Inhibitor of apoptosis 2 and TAK1-binding protein are components of the Imd pathway, which controls antimicrobial peptide expression in Drosophila. (PMID:16163390)
• dTAB2 is specifically required for PGN-induced activation of JNK and NF-kappaB signaling pathways. (PMID:16311020)
• VDAC2 and VDAC3 might have an alternative structural organization and different functions in outer dense fibers than in mitochondria (PMID:14739283)
• VDAC-2 inhibits the Bak-mediated apoptotic response via Bax (PMID:15757910)
• Results identify VDAC2 and aldolase A as membrane proteins of K562 cells with increased expression under iron deprivation. (PMID:18278581)
• The high abundance of VDAC2 mRNA seemed to have a positive correlation with low sperm motility in male infertility with idiopathic asthenozoospermia. (PMID:20809416)
• VDAC2 may facilitate mitochondrial Ca(2+) uptake and restrict Ca(2+) spark expansion without regulating activations of sparks under resting conditions. (PMID:21241999)
• distribution and function of VDAC2 in human spermatozoa (PMID:21347391)
• VP5-induced apoptosis during IBDV infection is mediated by interacting with VDAC2, a protein that appears to restrict viral replication via induction of cell death (PMID:22114330)
• The reconstitution of functional VDAC-2 in lauryldimethylamine-oxide (LDAO) detergent micelles and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) lipid bilayer nanodiscs, is reported. (PMID:22119777)
• Binding of VDAC2 enhances eNOS activity in the pulmonary circulation. (PMID:22842492)
• VDAC 1, 2, and 3 recruit Parkin to defective mitochondria to promote mitochondrial autophagy. (PMID:23060438)
• minor conformational variations in local residues are sufficient to define the membrane protein dynamics in hVDAC-2. (PMID:23873934)
• Cysteine residues impact the stability and micelle interaction dynamics of the human mitochondrial beta-barrel anion channel VDAC-2. (PMID:24642864)
• GSK-3beta translocates from the cytosol to mitochondria in a kinase activity- and VDAC2-dependent manner in which an N-terminal domain of GSK-3beta may function as a mitochondrial targeting sequence (PMID:25187518)
• These data suggest that an interaction between Mcl-1 and VDAC promotes lung cancer cell migration by a mechanism that involves Ca(2+)-dependent reactive oxygen species production. (PMID:25341036)
• RACK1 plays an antiapoptotic role during IBDV infection via interaction with VDAC2 and VP5. (PMID:25583988)
• Results show that in thyroid tumours and cell lines, VDAC2 is upregulated and BAK1 downregulated. Also, transient knockdown of VDAC2 promoted upregulation of the BAK1 expression, and increased susceptibility to sorafenib treatment. (PMID:25617717)
• Motifs of VDAC2 required for mitochondrial Bak import and tBid-induced apoptosis. (PMID:26417093)
• The evolutionary demand for the NTE in the presence of cysteines clearly emerges from our biochemical and functional studies, providing insight into factors that functionally demarcate hVDAC-2 from the other VDACs. (PMID:26487717)
• The works available on VDAC cysteines support the notion that VDAC1, VDAC2, and VDAC3 proteins are paralogs with a similar pore-function and slightly different, but important, ancillary biological functions. (Review) (PMID:26947058)
• VDAC2 ensures mitochondria-specific membrane association of Bax and in the absence of VDAC2 Bax localizes towards other cell compartments. Bax retrotranslocation is also regulated by nucleotides and calcium ions, suggesting a potential role of the transport of these ions through VDAC2 in Bax retrotranslocation. (PMID:27620692)
• Chinese men carrying VDAC2 variants may have a decreased or increased risk of abnormal semen parameters associated with male infertility. (PMID:27806320)
• High methylation of the VDAC2 promoter CpGs in men with asthenospermia (PMID:27892527)
• VDAC2 is a new glycolytic regulator controlling the phenotype transition between glioma stem cells and non-stem cells and may serves as a new prognostic indicator and a potential therapeutic target for glioma patients. (PMID:30250190)
• VDAC plasticity and stability in the mitochondrial outer membrane are modulated by physical properties of the bilayer (PMID:30503532)
• Study data support a role of VDAC2 as direct effector of ceramide-mediated cell death, providing a molecular framework for how ceramides exert their anti-neoplastic activity. (PMID:31015432)
• mitochondrial targeting domain peptide induces necrotic cell death by interaction with the VDAC2 protein. (PMID:31285435)
• VDAC2 role in the melanoma drug resistance to erastin.Erastin-induced resistance mediated by FOXM1-Nedd4-VDAC2/VDAC3 negative feedback loop in melanoma.Nedd4 ubiquitinates and degrades VDAC2. (PMID:31974380)
• Structure-based modeling of turnover of Bcl-2 family proteins bound to voltage-dependent anion channel 2 (VDAC2): Implications for the mechanisms of proapoptotic activation of Bak and Bax in vivo. (PMID:31981967)
• A High Resolution Mass Spectrometry Study Reveals the Potential of Disulfide Formation in Human Mitochondrial Voltage-Dependent Anion Selective Channel Isoforms (hVDACs). (PMID:32098132)
• Inflammatory IFIT3 renders chemotherapy resistance by regulating post-translational modification of VDAC2 in pancreatic cancer. (PMID:32641986)
• Expression of voltage-dependent anion channels in endometrial cancer and its potential prognostic significance. (PMID:32829673)
• Bisindolylpyrrole triggers transient mitochondrial permeability transitions to cause apoptosis in a VDAC1/2 and cyclophilin D-dependent manner via the ANT-associated pore. (PMID:33046783)
• Palmitoylated CKAP4 regulates mitochondrial functions through an interaction with VDAC2 at ER-mitochondria contact sites. (PMID:33067255)
• BioID-based proteomic analysis of the Bid interactome identifies novel proteins involved in cell-cycle-dependent apoptotic priming. (PMID:33067418)
• Protein mass spectrometry reveals lycorine exerting anti-multiple-myeloma effect by acting on VDAC2 and causing mitochondrial abnormalities. (PMID:33386501)
• STING Suppresses Mitochondrial VDAC2 to Govern RCC Growth Independent of Innate Immunity. (PMID:36445063)
• TRIM8 promotes ovarian cancer proliferation and migration by targeting VDAC2 for ubiquitination and degradation. (PMID:38881325)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	vdac2	ENSDARG00000013623
mus_musculus	Vdac2	ENSMUSG00000021771
rattus_norvegicus	Vdac2	ENSRNOG00000013505
rattus_norvegicus	AABR07051831.1	ENSRNOG00000015854
drosophila_melanogaster	porin	FBGN0004363
drosophila_melanogaster	Porin2	FBGN0069354
drosophila_melanogaster	CG17140	FBGN0260453
drosophila_melanogaster	CG17139	FBGN0260454
caenorhabditis_elegans		WBGENE00019900

Paralogs (2): VDAC3 (ENSG00000078668), VDAC1 (ENSG00000213585)

Protein

Protein identifiers

Non-selective voltage-gated ion channel VDAC2 — P45880 (reviewed: P45880)

Alternative names: Outer mitochondrial membrane protein porin 2

All UniProt accessions (6): A0A024QZT0, A0A0A0MR02, A2A3S1, P45880, Q5JSD1, Q5JSD2

UniProt curated annotations — full annotation on UniProt →

Function. Non-selective voltage-gated ion channel that mediates the transport of anions and cations through the mitochondrion outer membrane and plasma membrane. The channel adopts an open conformation at zero mV and a closed conformation at both positive and negative potentials. There are two populations of channels; the main that functions in a lower open-state conductance with lower ion selectivity, that switch, in a voltage-dependent manner, from the open to a low-conducting ‘closed’ state and the other that has a normal ion selectivity in the typical high conductance, ‘open’ state. Binds various lipids, including the sphingolipid ceramide, the phospholipid phosphatidylcholine, and the sterols cholesterol and oxysterol. Binding of ceramide promotes the mitochondrial outer membrane permeabilization (MOMP) apoptotic pathway. Associates with the translocase of the outer mitochondrial membrane (TOM) complex and PINK1 kinase at depolarized mitochondria, this interaction stabilizes PINK1 at the outer mitochondrial membrane and triggers downstream mitophagy by the recruitment of the E3 ubiquitin ligase PRKN. Catalyzes the scrambling of phospholipids across the outer mitochondrial membrane; the mechanism is unrelated to channel activity and is capable of translocating both anionic and zwitterionic phospholipids.

Subunit / interactions. Monomer, homodimer and higher order oligomers; formation of higher order structures is necessary for scramblase activity. Interacts with ARMC12 in a TBC1D21-dependent manner. Interacts with KLC3. Interacts with SPATA33. Interacts with PPP3CC in a SPATA33-dependent manner. As a homodimer, interacts with the TOM complex. Upon mitochondrial depolarization, the TOM-VDAC assembly interacts with PINK1; the interaction stabilizes PINK1 at the outer mitochondrial membrane and triggers downstream mitophagy.

Subcellular location. Mitochondrion outer membrane. Membrane.

Tissue specificity. Expressed in erythrocytes (at protein level). Expressed in all tissues examined.

Post-translational modifications. Ubiquitinated by PRKN during mitophagy, leading to its degradation and enhancement of mitophagy. Deubiquitinated by USP30.

Domain organisation. Consists mainly of a membrane-spanning beta-barrel formed by 19 beta-strands.

Similarity. Belongs to the eukaryotic mitochondrial porin family.

Isoforms (3)

UniProt ID	Names	Canonical?
P45880-3	3	yes
P45880-1	1
P45880-2	2

RefSeq proteins (8): NP_001171712, NP_001171752, NP_001311016, NP_001311017, NP_001311018, NP_001311019, NP_001378892, NP_003366 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001925	Porin_Euk	Family
IPR023614	Porin_dom_sf	Homologous_superfamily
IPR027246	Porin_Euk/Tom40	Family

Pfam: PF01459

Catalyzed reactions (Rhea), 5 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)
• chloride(in) = chloride(out) (RHEA:29823)
• a 1,2-diacyl-sn-glycero-3-phosphocholine(in) = a 1,2-diacyl-sn-glycero-3-phosphocholine(out) (RHEA:38571)
• a 1,2-diacyl-sn-glycero-3-phospho-L-serine(in) = a 1,2-diacyl-sn-glycero-3-phospho-L-serine(out) (RHEA:38663)
• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol)(in) = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol)(out) (RHEA:38691)

UniProt features (102 total): topological domain 20, transmembrane region 19, strand 18, cross-link 9, modified residue 8, binding site 7, turn 7, helix 4, short sequence motif 2, splice variant 2, initiator methionine 1, chain 1, intramembrane region 1, site 1, sequence variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9EII	ELECTRON MICROSCOPY	2.75
9EIH	ELECTRON MICROSCOPY	3.1
9EIJ	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P45880-F1	92.28	0.83

Functional residue map

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

Catalytic / active sites (1): 84 (involved in ceramide and phosphatidylcholine binding)

Ligand- & substrate-binding residues (7): 23; 31; 253; 254; 255; 272; 275

Post-translational modifications (17): 2, 31, 31, 78, 118, 120, 251, 277, 31, 64, 72, 120, 121, 124, 172, 277, 285

Mutagenesis-validated functional residues (1):

Position	Phenotype
84	abolishes ceramide and phosphatidylcholine binding. decreases apoptosis frequency following mitochondrial targeting of c

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-5205685	PINK1-PRKN Mediated Mitophagy
R-HSA-5689880	Ub-specific processing proteases
R-HSA-8949215	Mitochondrial calcium ion transport

MSigDB gene sets: 322 (showing top): GOBP_SINGLE_FERTILIZATION, MORF_DNMT1, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_10, GOCC_SECRETORY_GRANULE, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, MORF_RRM1, MORF_HDAC1, GOBP_PLASMA_MEMBRANE_ORGANIZATION, MORF_UBE2N, DITTMER_PTHLH_TARGETS_UP, HSIAO_HOUSEKEEPING_GENES, TGACCTY_ERR1_Q2, MORF_HDAC2, MODULE_16, GOBP_REGULATION_OF_MEMBRANE_LIPID_DISTRIBUTION

GO Biological Process (10): monoatomic anion transport (GO:0006820), binding of sperm to zona pellucida (GO:0007339), phospholipid translocation (GO:0045332), mitochondrial outer membrane permeabilization (GO:0097345), mitochondrial transmembrane transport (GO:1990542), monoatomic ion transport (GO:0006811), lipid transport (GO:0006869), plasma membrane phospholipid scrambling (GO:0017121), transmembrane transport (GO:0055085), monoatomic anion transmembrane transport (GO:0098656)

GO Molecular Function (12): voltage-gated monoatomic ion channel activity (GO:0005244), ATP binding (GO:0005524), oxysterol binding (GO:0008142), voltage-gated monoatomic anion channel activity (GO:0008308), porin activity (GO:0015288), cholesterol binding (GO:0015485), phospholipid scramblase activity (GO:0017128), phosphatidylcholine binding (GO:0031210), ceramide binding (GO:0097001), nucleotide binding (GO:0000166), protein binding (GO:0005515), lipid binding (GO:0008289)

GO Cellular Component (10): acrosomal vesicle (GO:0001669), nucleus (GO:0005634), mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), membrane (GO:0016020), mitochondrial membrane (GO:0031966), mitochondrial nucleoid (GO:0042645), membrane raft (GO:0045121), pore complex (GO:0046930), sperm midpiece (GO:0097225)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Mitophagy	1
Deubiquitination	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	3
sterol binding	2
binding	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
mitochondrion	2
monoatomic ion transport	1
sperm-egg recognition	1
phospholipid transport	1
lipid translocation	1
apoptotic signaling pathway	1
positive regulation of mitochondrial membrane permeability involved in apoptotic process	1
mitochondrial transport	1
transmembrane transport	1
lipid localization	1
plasma membrane organization	1
phospholipid translocation	1
cellular process	1
monoatomic anion transport	1
monoatomic ion transmembrane transport	1
monoatomic ion channel activity	1
voltage-gated channel activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
voltage-gated monoatomic ion channel activity	1
monoatomic anion channel activity	1
wide pore channel activity	1
alcohol binding	1
plasma membrane phospholipid scrambling	1
intramembrane lipid carrier activity	1
phospholipid binding	1
cation binding	1
quaternary ammonium group binding	1
sphingolipid binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
secretory granule	1
cytoplasm	1
mitochondrial membrane	1
organelle outer membrane	1

Protein interactions and networks

STRING

3348 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VDAC2	CYCS	P00001	947
VDAC2	SLC25A6	P12236	879
VDAC2	GK2	Q14410	822
VDAC2	GK	P32189	817
VDAC2	BCL2	P10415	813
VDAC2	ITPR3	Q14573	780
VDAC2	ITPR1	Q14643	768
VDAC2	TOMM22	Q9NS69	757
VDAC2	PFKP	Q01813	751
VDAC2	MCL1	Q07820	730
VDAC2	HSPA5	P11021	714
VDAC2	SLC25A5	P05141	699
VDAC2	PHB1	P35232	698
VDAC2	MFN2	O95140	696
VDAC2	BCL2L1	Q07817	673

IntAct

329 interactions, top by confidence:

A	B	Type	Score
TRIM33	TRIM24	psi-mi:“MI:0914”(association)	0.790
HTT	VDAC2	psi-mi:“MI:0915”(physical association)	0.670
EMC1	EMC8	psi-mi:“MI:0914”(association)	0.640
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
VDAC1	VDAC2	psi-mi:“MI:0915”(physical association)	0.620
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
VDAC2	VDAC3	psi-mi:“MI:0915”(physical association)	0.560
AGTR1	VDAC2	psi-mi:“MI:0915”(physical association)	0.560
VDAC2	APBB2	psi-mi:“MI:0915”(physical association)	0.560
VDAC2	CTSD	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (612): VDAC2 (Affinity Capture-MS), VDAC2 (Affinity Capture-MS), VDAC2 (Affinity Capture-MS), VDAC2 (Affinity Capture-MS), ARF5 (Affinity Capture-MS), ATP5A1 (Co-fractionation), ATP5B (Co-fractionation), ATP5D (Co-fractionation), ATP5I (Co-fractionation), ATP5O (Co-fractionation), ATP6V0D1 (Co-fractionation), BCAP31 (Co-fractionation), CISD1 (Co-fractionation), CISD2 (Co-fractionation), CLTC (Co-fractionation)

ESM2 similar proteins: A0A1S4A695, A0A6P7EFR0, A4F267, A6QR22, O97556, P07144, P21796, P42055, P42056, P45879, P45880, P50395, P50397, P50399, P62495, P62496, P62497, P62498, P68002, P68003, P81004, P81155, P82013, P86223, Q0VCK5, Q0VCX5, Q1W374, Q1W375, Q1W376, Q1W377, Q29380, Q5R4C7, Q5R7V4, Q5RCE1, Q5U2Q7, Q60930, Q60931, Q60932, Q61598, Q6Q7J2

Diamond homologs: A0A6P7EFR0, P07144, P21796, P45879, P45880, P68002, P68003, P81004, P81155, P82013, P82945, P83781, P86223, Q21752, Q29380, Q5R7V4, Q60930, Q60931, Q60932, Q94920, Q9MZ13, Q9MZ15, Q9MZ16, Q9R1Z0, Q9TT13, Q9TT15, Q9Y277, Q9Z2L0, P04840, P40478, Q9P544, Q7F4F8

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 147 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.

GO biological processes:

GO term	Partners	Fold	FDR
ERAD pathway	6	9.0×	9e-03
endoplasmic reticulum to Golgi vesicle-mediated transport	7	7.9×	9e-03
positive regulation of apoptotic process	12	5.6×	9e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	34
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2008 predictions. Top by Δscore:

Variant	Effect	Δscore
10:75211185:GCGTC:G	donor_gain	1.0000
10:75211187:GTC:G	donor_gain	1.0000
10:75211188:TC:T	donor_gain	1.0000
10:75211190:G:GG	donor_gain	1.0000
10:75212225:A:AG	acceptor_gain	1.0000
10:75212226:C:G	acceptor_gain	1.0000
10:75212226:CCAGC:C	acceptor_loss	1.0000
10:75212227:CAG:C	acceptor_loss	1.0000
10:75212228:A:AG	acceptor_gain	1.0000
10:75212228:AG:A	acceptor_loss	1.0000
10:75212229:G:GA	acceptor_gain	1.0000
10:75212229:G:T	acceptor_loss	1.0000
10:75212229:GC:G	acceptor_gain	1.0000
10:75212229:GCA:G	acceptor_gain	1.0000
10:75212229:GCAA:G	acceptor_gain	1.0000
10:75212229:GCAAT:G	acceptor_gain	1.0000
10:75212231:A:AG	acceptor_gain	1.0000
10:75212293:GAT:G	donor_gain	1.0000
10:75212295:TTTGG:T	donor_loss	1.0000
10:75212296:TTGGT:T	donor_loss	1.0000
10:75212297:TGG:T	donor_loss	1.0000
10:75212298:GGTAA:G	donor_loss	1.0000
10:75212299:G:C	donor_loss	1.0000
10:75212299:G:GG	donor_gain	1.0000
10:75212300:T:A	donor_loss	1.0000
10:75219059:TTA:T	acceptor_loss	1.0000
10:75219061:A:AC	acceptor_loss	1.0000
10:75219061:A:AG	acceptor_gain	1.0000
10:75219062:G:GG	acceptor_gain	1.0000
10:75219062:GGA:G	acceptor_gain	1.0000

AlphaMissense

1912 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:75219168:T:A	W86R	1.000
10:75219168:T:C	W86R	1.000
10:75219323:T:C	L108P	1.000
10:75212262:G:C	G22R	0.999
10:75219067:T:C	F52S	0.999
10:75219112:G:A	G67E	0.999
10:75220754:G:A	G123D	0.999
10:75220864:T:A	W160R	0.999
10:75220864:T:C	W160R	0.999
10:75220868:T:C	L161P	0.999
10:75220871:C:A	A162D	0.999
10:75220873:G:C	G163R	0.999
10:75220874:G:A	G163D	0.999
10:75220927:G:C	A181P	0.999
10:75222268:T:C	F201L	0.999
10:75222270:T:A	F201L	0.999
10:75222270:T:G	F201L	0.999
10:75222277:T:C	S204P	0.999
10:75222328:T:A	W221R	0.999
10:75222328:T:C	W221R	0.999
10:75222365:C:A	A233E	0.999
10:75222367:G:C	A234P	0.999
10:75222368:C:A	A234D	0.999
10:75229651:T:A	V248D	0.999
10:75230907:T:C	L268P	0.999
10:75212263:G:T	G22V	0.998
10:75214039:T:C	L40P	0.998
10:75219079:G:A	G56D	0.998
10:75219111:G:A	G67R	0.998
10:75219111:G:C	G67R	0.998

dbSNP variants (sampled 300 via entrez): RS1000172779 (10:75222818 A>G), RS1000198036 (10:75216422 A>G,T), RS1000364246 (10:75228654 C>A), RS1000443962 (10:75216738 C>T), RS1000669054 (10:75222534 T>C), RS1000818800 (10:75224475 C>T), RS1000967340 (10:75227187 A>G), RS1001062315 (10:75226874 G>A,T), RS1001112442 (10:75229985 ATTT>A), RS1001203695 (10:75215287 G>A,C,T), RS1001271958 (10:75221027 G>A), RS1001374606 (10:75218445 C>T), RS1001388477 (10:75210774 C>G,T), RS1001444172 (10:75215528 A>C,G), RS1001479362 (10:75218889 A>G)

Disease associations

OMIM: gene MIM:193245 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): severe combined immunodeficiency (MONDO:0015974)

Orphanet (1): Severe combined immunodeficiency (Orphanet:183660)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0004430	Severe combined immunodeficiency

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D016511	Severe Combined Immunodeficiency	C16.320.798.750; C16.614.815; C18.452.284.800; C20.673.795.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6190 (SINGLE PROTEIN)

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.00	Kd	100	nM	ERASTIN
5.50	Kd	3151	nM	CHEMBL3752910
5.50	ED50	3151	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 8 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[1-[4-[2-(4-chlorophenoxy)acetyl]piperazin-1-yl]ethyl]-3-(2-ethoxyphenyl)quinazolin-4-one	327395: Binding affinity to human VDAC2	kd	0.1000	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149761: Binding affinity to human VDAC2 incubated for 45 mins by Kinobead based pull down assay	kd	3.1513	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol F	increases expression, affects cotreatment, decreases expression	2
bisphenol A	increases expression, affects cotreatment, decreases expression	2
sodium arsenite	increases expression	2
bisphenol S	affects cotreatment, increases methylation, increases expression	2
GSK-J4	increases expression	1
ME-344	affects response to substance, affects localization, decreases reaction, increases abundance, affects binding	1
FR900359	increases phosphorylation	1
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
uranyl acetate	affects expression	1
ferric ammonium citrate	decreases reaction, increases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction	1
potassium chromate(VI)	affects cotreatment, increases expression	1
4-hydroxy-2-nonenal	affects binding	1
diallyl trisulfide	decreases expression	1
epigallocatechin gallate	increases expression, affects cotreatment	1
cyanoginosin LR	affects binding, decreases reaction, increases reaction	1
CD 437	decreases expression	1
deguelin	increases expression	1
3-(4’-hydroxy-3’-adamantylbiphenyl-4-yl)acrylic acid	decreases expression	1
erastin	affects binding, decreases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
quinocetone	decreases reaction, increases reaction, affects localization, affects binding	1
pyrachlostrobin	increases expression	1
benzyloxycarbonyl-valyl-alanyl-aspartic acid	affects binding, decreases reaction, increases reaction	1
jinfukang	decreases expression	1
picoxystrobin	increases expression	1
bisphenol AF	increases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4341381	Binding	Binding affinity to VDAC2 in human A549 cells lysates grown on SILAC media at 10 uM incubated for 1 hr by LC-MS/MS analysis	Profiling withanolide A for therapeutic targets in neurodegenerative diseases. — Bioorg Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1RB	Abcam K-562 VDAC2 KO	Cancer cell line	Female
CVCL_D2MY	Abcam Raji VDAC2 KO	Cancer cell line	Male
CVCL_WQ80	Abcam Jurkat VDAC2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00220766	PHASE3	COMPLETED	Rapid Infusion of Immune Globulin Intravenous (Human) In Primary Immunodeficiency Patients
NCT01420627	PHASE3	COMPLETED	EZN-2279 in Patients With ADA-SCID
NCT06940570	PHASE3	SUSPENDED	Methadone as an Alternative Treatment for Children Underdoing HSCT
NCT00000603	PHASE2	COMPLETED	Cord Blood Stem Cell Transplantation Study (COBLT)
NCT00794508	PHASE2	COMPLETED	MND-ADA Transduction of CD34+ Cells From Children With ADA-SCID
NCT01182675	PHASE2	TERMINATED	Hematopoietic Stem Cell Transplantation (HSCT) for Children With SCID Utilizing Alemtuzumab, Plerixafor & Filgrastim
NCT01529827	PHASE2	COMPLETED	Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT01821781	PHASE2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT02177760	PHASE2	WITHDRAWN	Sirolimus Prophylaxis for aGVHD in TME SCID
NCT03619551	PHASE2	ACTIVE_NOT_RECRUITING	Conditioning SCID Infants Diagnosed Early
NCT00008450	PHASE1	COMPLETED	Total-Body Irradiation Followed By Cyclosporine and Mycophenolate Mofetil in Treating Patients With Severe Combined Immunodeficiency Undergoing Donor Bone Marrow Transplant
NCT00028236	PHASE1	COMPLETED	Stem Cell Gene Therapy to Treat X-Linked Severe Combined Immunodeficiency (XSCID)
NCT00152100	PHASE1	COMPLETED	Transplantation of Hematopoietic Cells in Children With Severe Combined Immunodeficiency Syndrome
NCT02860559	PHASE1	UNKNOWN	Safety and Early Efficacy Study of TBX-1400 in Patients With Severe Combined Immunodeficiency
NCT01019876	PHASE2/PHASE3	COMPLETED	Risk-Adapted Allogeneic Stem Cell Transplantation For Mixed Donor Chimerism In Patients With Non-Malignant Diseases
NCT00228852	PHASE1/PHASE2	COMPLETED	IMM 0212: Busulfan With Fludarabine and Antithymocyte Globulin as Preparative Therapy for Hematopoietic Stem Cell Transplant for the Treatment of Severe Congenital T-Cell Immunodeficiency
NCT00579137	PHASE1/PHASE2	TERMINATED	Allogeneic SCT Of Pts With SCID And Other Primary Immunodeficiency Disorders
NCT01129544	PHASE1/PHASE2	COMPLETED	Gene Transfer for Severe Combined Immunodeficiency, X-linked (SCID-X1) Using a Self-inactivating (SIN) Gammaretroviral Vector
NCT01852370	PHASE1/PHASE2	ENROLLING_BY_INVITATION	Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases
NCT02127892	PHASE1/PHASE2	TERMINATED	SCID Bu/Flu/ATG Study With T Cell Depletion
NCT02963064	PHASE1/PHASE2	TERMINATED	JSP191 Antibody Targeting Conditioning in SCID Patients
NCT03513328	PHASE1/PHASE2	COMPLETED	Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation
NCT03538899	PHASE1/PHASE2	RECRUITING	Autologous Gene Therapy for Artemis-Deficient SCID
NCT03597594	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Haplocompatible Transplant Using TCRα/β Depletion Followed by CD45RA-Depleted Donor Lymphocyte Infusions for Severe Combined Immunodeficiency (SCID)
NCT00001255	Not specified	COMPLETED	Gene Transfer Therapy for Severe Combined Immunodeficieny Disease (SCID) Due to Adenosine Deaminase (ADA) Deficiency: A Natural History Study
NCT00006054	Not specified	TERMINATED	Allogeneic Bone Marrow Transplantation in Patients With Primary Immunodeficiencies
NCT00006335	Not specified	COMPLETED	Influences on Female Adolescents’ Decisions Regarding Testing for Carrier Status of XSCID
NCT00055172	Not specified	RECRUITING	Genetic Basis of Immunodeficiency
NCT00695279	Not specified	COMPLETED	Long Term Follow Up Of Patients Who Have Received Gene Therapy Or Gene Marked Products
NCT00845416	Not specified	COMPLETED	Newborn Screening for Severe Combined Immunodeficiency (SCID) in a High-Risk Population
NCT01186913	Not specified	ENROLLING_BY_INVITATION	Natural History Study of SCID Disorders
NCT01346150	Not specified	UNKNOWN	Patients Treated for SCID (1968-Present)
NCT01652092	Not specified	ACTIVE_NOT_RECRUITING	Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies
NCT01953016	Not specified	COMPLETED	Participation in a Research Registry for Immune Disorders
NCT02231983	Not specified	UNKNOWN	Clinical Characteristics and Genetic Profiles of Severe Combined Immunodeficiency in China
NCT02590328	Not specified	COMPLETED	Neonatal Screening of Severe Combined Immunodeficiencies
NCT04049084	Not specified	ENROLLING_BY_INVITATION	An Observational LTFU Study for Patients Previously Treated With Autologous ex Vivo Gene Therapy for ADA-SCID
NCT04172181	Not specified	UNKNOWN	Multi-center Clinical Study of Cord Blood Stem Cell Transplantation for SCID
NCT04246840	Not specified	COMPLETED	Study Through Imaging of Visceral Lymphoid Organs in Patients With SCID Who Have Recieved Bone Marrow Allograft
NCT04331483	Not specified	WITHDRAWN	A Study to Assess a Physical Activity Program in Children, Adolescents and Young Adults Requiring Hematopoietic Stem Cell Allografts