VAPA

Summary

VAPA (VAMP associated protein A, HGNC:12648) is a protein-coding gene on chromosome 18p11.22, encoding Vesicle-associated membrane protein-associated protein A (Q9P0L0). Endoplasmic reticulum (ER)-anchored protein that mediates the formation of contact sites between the ER and endosomes via interaction with FFAT motif-containing proteins such as STARD3 or WDR44.

The protein encoded by this gene is a type IV membrane protein. It is present in the plasma membrane and intracellular vesicles. It may also be associated with the cytoskeleton. This protein may function in vesicle trafficking, membrane fusion, protein complex assembly and cell motility. Alternative splicing occurs at this locus and two transcript variants encoding distinct isoforms have been identified.

Source: NCBI Gene 9218 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 52 total — 1 likely-pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes
• MANE Select transcript: NM_194434

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12648
Approved symbol	VAPA
Name	VAMP associated protein A
Location	18p11.22
Locus type	gene with protein product
Status	Approved
Aliases	hVAP-33, VAP-A
Ensembl gene	ENSG00000101558
Ensembl biotype	protein_coding
OMIM	605703
Entrez	9218

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 14 protein_coding, 4 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000340541, ENST00000400000, ENST00000577539, ENST00000577901, ENST00000578314, ENST00000583475, ENST00000583879, ENST00000584796, ENST00000585042, ENST00000897659, ENST00000897660, ENST00000897661, ENST00000897662, ENST00000928106, ENST00000928107, ENST00000928108, ENST00000971047, ENST00000971048, ENST00000971049, ENST00000971050, ENST00000971051

RefSeq mRNA: 2 — MANE Select: NM_194434 NM_003574, NM_194434

CCDS: CCDS11847, CCDS11848

Canonical transcript exons

ENST00000400000 — 6 exons

Exon	Start	End
ENSE00001184229	9914016	9914335
ENSE00001321272	9954053	9960021
ENSE00003462588	9950395	9950568
ENSE00003634602	9936986	9937066
ENSE00003643246	9931810	9931962
ENSE00003666267	9936110	9936213

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.64.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 153.9381 / max 1188.6995, expressed in 1828 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
169390	119.0437	1827
169393	32.0223	1818
169391	0.9758	470
208496	0.8051	484
169392	0.3279	132
208495	0.3094	113
169394	0.2375	83
169395	0.2164	57

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.64	gold quality
cranial nerve II	UBERON:0000941	99.36	gold quality
adrenal tissue	UBERON:0018303	99.33	gold quality
right adrenal gland	UBERON:0001233	99.21	gold quality
right adrenal gland cortex	UBERON:0035827	99.19	gold quality
left adrenal gland	UBERON:0001234	99.13	gold quality
adrenal gland	UBERON:0002369	99.08	gold quality
adrenal cortex	UBERON:0001235	99.06	gold quality
left adrenal gland cortex	UBERON:0035825	99.03	gold quality
gingival epithelium	UBERON:0001949	99.02	gold quality
pons	UBERON:0000988	98.99	gold quality
parotid gland	UBERON:0001831	98.99	gold quality
esophagus squamous epithelium	UBERON:0006920	98.98	gold quality
squamous epithelium	UBERON:0006914	98.94	gold quality
gingiva	UBERON:0001828	98.90	gold quality
adult organism	UBERON:0007023	98.87	gold quality
cervix squamous epithelium	UBERON:0006922	98.86	gold quality
islet of Langerhans	UBERON:0000006	98.85	gold quality
rectum	UBERON:0001052	98.85	gold quality
epithelium of bronchus	UBERON:0002031	98.85	gold quality
epithelium of esophagus	UBERON:0001976	98.82	gold quality
bronchus	UBERON:0002185	98.82	gold quality
bronchial epithelial cell	CL:0002328	98.81	gold quality
heart right ventricle	UBERON:0002080	98.81	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.80	gold quality
ventricular zone	UBERON:0003053	98.73	gold quality
choroid plexus epithelium	UBERON:0003911	98.73	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.71	gold quality
gall bladder	UBERON:0002110	98.68	gold quality
amniotic fluid	UBERON:0000173	98.67	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-10042	yes	13.58
E-CURD-46	no	4.98
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR

miRNA regulators (miRDB)

268 targeting VAPA, 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-8485	100.00	77.57	4731
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4481	100.00	66.42	1669
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-548N	99.98	71.94	4170

Literature-anchored findings (GeneRIF, showing 29)

• protein-protein interactions among the various HCV NS proteins and hVAP-33 are important for the formation of HCV replication complex (PMID:15016871)
• Our results provide suggestive evidence of an association between SNPs in the 3’UTR of the VAPA gene and bipolar disorder. (PMID:18665321)
• Data show that overexpression of VAPA and VAPB causes retention of ER membrane proteins by impeding lateral diffusion and their incorporation into transport vesicles. (PMID:18713837)
• VAP-A is an important regulator both of the subcellular localization of protrudin and of its ability to stimulate neurite outgrowth. (PMID:19289470)
• GLTP and VAP-A were shown to interact. (PMID:19665998)
• Electrostatic interaction between oxysterol-binding protein and VAMP-associated protein A revealed by NMR and mutagenesis studies. (PMID:20178991)
• three conserved prolines in VAPA and Scs2p confers less vulnerability to mutations equivalent to the amyotrophic lateral sclerosis causing mutation as compared with VAPB, which has only two conserved prolines. (PMID:21144830)
• Data show that the methylated VAPA-APCDD1 DNA in maternal plasma is predominantly derived from the fetus, and this novel fetal epigenetic marker in maternal plasma is useful for the noninvasive detection of fetal trisomy 18. (PMID:21152411)
• Viperin inhibits hepatitis C virus replication by interfering with binding of NS5A to host protein VAP-33. (PMID:21957124)
• STARD3 or STARD3NL and VAP form a novel molecular tether between late endosomes and the endoplasmic reticulum. (PMID:24105263)
• GPS2 is required for the association of viral NS5A with VAP-A and hepatitis C virus replication. (PMID:24223774)
• phosphorylation of CERT at the FFAT motif-adjacent serine affects its affinity for VAP, which may regulate the inter-organelle trafficking of ceramide in response to the perturbation of cellular sphingomyelin and/or other sphingolipids (PMID:24569996)
• phosphorylation of ORP3 controls its association with VAPA. Furthermore, ORP3-VAPA complexes stimulate R-Ras signaling. (PMID:25447204)
• The effects of sterol manipulation of HuH7 cells on complexes of established sterol-binding Oxysterol-binding protein related proteins with their endoplasmic reticulum receptor, VAMP-associated protein A (VAPA), were examined. (PMID:25681634)
• Our work revealed that VAP-A/B knockdown impaired the processing and secretion of PAUF, which is one of the cargo proteins of carriers of the trans-Golgi network to the cell surface. (PMID:26490117)
• Effects of the combined absence of VAPA and VAPB in human cells were studied; cells lacking VAP accumulate high levels of PI4P, actin comets, and trans-Golgi proteins on endosomes. Such defects are mimicked by downregulation of OSBP, a VAP interactor and PI4P transporter that participates in VAP-dependent endoplasmic reticulum-endosomes tethers. (PMID:27419871)
• VAP-ACBD5-mediated contact between the endoplasmic reticulum and peroxisomes mediate organelle maintenance and lipid homeostasis. (PMID:28108526)
• the component proteins of the machinery, OSBP, VAP, SAC1, and PITPNB, are all essential host factors for AiV replication. Importantly, the machinery is directly recruited to the RNA replication sites through previously unknown interactions of VAP/OSBP/SAC1 with the AiV proteins and with ACBD3. (PMID:29367253)
• Thus, we characterized here MOSPD2, a novel tethering component related to VAP proteins(VAP-A and VAP-B), bridging the endoplasmic reticulum with a variety of distinct organelles. (PMID:29858488)
• The silencing of VAP-A or ORP3 abrogated the association of Rab7-positive late endosomes with nuclear envelope invaginations and, hence, the transport of endocytosed EV-derived components to the nucleoplasm of recipient cells. (PMID:30018135)
• VAP proteins (VAPs) mediate ER to Golgi tethering and their loss may affect phosphatidylinositol-4-phosphate (PtdIns4P) transfer between these organelles. Loss of VAPs elevates PtdIns4P levels in the Golgi, leading to an expansion of the endosomal pool derived from the Golgi. (PMID:30741620)
• Circular RNA VAPA is up-regulated in colorectal cancer and exerts oncogenic properties by sponging miR-101. (PMID:30797148)
• CALCOCO1 acts with VAMP-associated proteins to mediate ER-phagy. (PMID:32525583)
• CircVAPA exerts oncogenic property in non-small cell lung cancer by the miR-876-5p/WNT5A axis. (PMID:33619796)
• Role of Vesicle-Associated Membrane Protein-Associated Proteins (VAP) A and VAPB in Nuclear Egress of the Alphaherpesvirus Pseudorabies Virus. (PMID:34200728)
• Sequence requirements of the FFAT-like motif for specific binding to VAP-A are revealed by NMR. (PMID:34312846)
• VAP-A intrinsically disordered regions enable versatile tethering at membrane contact sites. (PMID:36693319)
• Analysis of small EV proteomes reveals unique functional protein networks regulated by VAP-A. (PMID:37926697)
• Cancer-associated fibroblasts derived exosomal LINC01833 promotes the occurrence of non-small cell lung cancer through miR-335-5p -VAPA axis. (PMID:39152098)

Cross-species orthologs

13 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000027824
danio_rerio	vapal	ENSDARG00000115862
mus_musculus	Vapa	ENSMUSG00000024091
rattus_norvegicus	Mospd4	ENSRNOG00000003575
rattus_norvegicus	Vapa	ENSRNOG00000014765
drosophila_melanogaster	fan	FBGN0028379
drosophila_melanogaster	Vap33	FBGN0029687
caenorhabditis_elegans		WBGENE00010254
caenorhabditis_elegans	vpr-1	WBGENE00018008
caenorhabditis_elegans		WBGENE00018354
caenorhabditis_elegans		WBGENE00018840
caenorhabditis_elegans		WBGENE00021428
caenorhabditis_elegans		WBGENE00022546

Paralogs (1): VAPB (ENSG00000124164)

Protein

Protein identifiers

Vesicle-associated membrane protein-associated protein A — Q9P0L0 (reviewed: Q9P0L0)

Alternative names: 33 kDa VAMP-associated protein

All UniProt accessions (2): Q9P0L0, J3QKM9

UniProt curated annotations — full annotation on UniProt →

Function. Endoplasmic reticulum (ER)-anchored protein that mediates the formation of contact sites between the ER and endosomes via interaction with FFAT motif-containing proteins such as STARD3 or WDR44. STARD3-VAPA interaction enables cholesterol transfer from the ER to endosomes. Via interaction with WDR44 participates in neosynthesized protein export. In addition, recruited to the plasma membrane through OSBPL3 binding. The OSBPL3-VAPA complex stimulates RRAS signaling which in turn attenuates integrin beta-1 (ITGB1) activation at the cell surface. With OSBPL3, may regulate ER morphology. May play a role in vesicle trafficking.

Subunit / interactions. Homodimer; disulfide-linked. Heterodimer with VAPB. Interacts with VAMP1, VAMP2, STX1A, BET1, SEC22C and with the C-terminal domain of OCLN. Interacts (via MSP domain) with OSBPL1A (via FFAT motif). Interacts (via MSP domain) with ZFYVE27; may retain ZFYVE27 in the endoplasmic reticulum and regulate its function in cell projections formation. Interacts with OSBP. Interacts (via C-terminus) with RSAD2/viperin (via C-terminus). Interacts with IFITM3. Interacts with OSBPL3 (phosphorylated form). Interacts with KIF5A in a ZFYVE27-dependent manner. Interacts (via MSP domain) with STARD3 (via phosphorylated FFAT motif); this interaction recruits VAPA to the endosome. Interacts with STARD3NL (via FFAT motif). Interacts with CERT1. Interacts with PLEKHA3 and SACM1L to form a ternary complex. Interacts with VPS13A (via FFAT motif). Interacts with RB1CC1 (via phosphorylated FFAT motif), MIGA2 (via phosphorylated FFAT motif), RMDN3 (via phosphorylated FFAT motif), KCNB1 (via phosphorylated FFAT motif) and KCNB2 (via phosphorylated FFAT motif). Interacts (via MSP domain) with WDR44 (via FFAT-like motif); the interactions connect the endoplasmic reticulum (ER) with the endosomal tubule. (Microbial infection) Interacts with HCV protein NS5A and NS5B.

Subcellular location. Endoplasmic reticulum membrane. Cell membrane. Cell junction. Tight junction. Nucleus membrane.

Tissue specificity. Ubiquitous.

Domain organisation. The MSP domain binds the FFAT motif of many proteins.

Similarity. Belongs to the VAMP-associated protein (VAP) (TC 9.B.17) family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9P0L0-1	1	yes
Q9P0L0-2	2

RefSeq proteins (2): NP_003565, NP_919415* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000535	MSP_dom	Domain
IPR008962	PapD-like_sf	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR016763	VAP	Family

Pfam: PF00635

UniProt features (38 total): strand 8, modified residue 7, mutagenesis site 4, sequence variant 2, sequence conflict 2, helix 2, region of interest 2, initiator methionine 1, chain 1, disulfide bond 1, splice variant 1, topological domain 1, transmembrane region 1, turn 1, domain 1, coiled-coil region 1, compositionally biased region 1, site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6TQR	X-RAY DIFFRACTION	1.85
2RR3	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P0L0-F1	79.32	0.44

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): 50 (involved in binding the phosphorylated serine of the phospho-ffat motif)

Post-translational modifications (7): 2, 125, 166, 170, 214, 216, 219

Disulfide bonds (1): 60

Mutagenesis-validated functional residues (4):

Position	Phenotype
1–151	impaired interaction with wdr44.
50	impairs the interaction of the msp domain with the phosphorylated ffat motif of stard3. does not affect its ability to i
94	alters interaction with zfyve27, impairs interaction with wdr44 and prevents binding to the ffat motif in target protein
96	alters interaction with zfyve27, impairs interaction with wdr44 and prevents binding to the ffat motif in target protein

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1660661	Sphingolipid de novo biosynthesis
R-HSA-6798695	Neutrophil degranulation
R-HSA-9609523	Insertion of tail-anchored proteins into the endoplasmic reticulum membrane

MSigDB gene sets: 335 (showing top): AP1_01, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, TAATAAT_MIR126, REACTOME_INNATE_IMMUNE_SYSTEM, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, GOBP_VESICLE_ORGANIZATION, CMYB_01, GOBP_SPHINGOMYELIN_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_MEMBRANE_FUSION, GOBP_MODULATION_OF_PROCESS_OF_ANOTHER_ORGANISM, GOBP_NEUROGENESIS, KEGG_TIGHT_JUNCTION

GO Biological Process (15): sphingomyelin biosynthetic process (GO:0006686), endoplasmic reticulum to Golgi vesicle-mediated transport (GO:0006888), phospholipid transport (GO:0015914), sterol transport (GO:0015918), viral release from host cell (GO:0019076), cholesterol transport (GO:0030301), neuron projection development (GO:0031175), ceramide transport (GO:0035627), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), host-mediated suppression of viral genome replication (GO:0044828), host-mediated activation of viral genome replication (GO:0044829), membrane fusion (GO:0061025), obsolete endoplasmic reticulum-plasma membrane tethering (GO:0061817), protein localization to endoplasmic reticulum (GO:0070972), COPII-coated vesicle budding (GO:0090114)

GO Molecular Function (8): microtubule binding (GO:0008017), protein domain specific binding (GO:0019904), FFAT motif binding (GO:0033149), protein homodimerization activity (GO:0042803), protein-membrane adaptor activity (GO:0043495), cadherin binding (GO:0045296), protein heterodimerization activity (GO:0046982), protein binding (GO:0005515)

GO Cellular Component (14): Golgi membrane (GO:0000139), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), plasma membrane (GO:0005886), bicellular tight junction (GO:0005923), microtubule cytoskeleton (GO:0015630), nuclear membrane (GO:0031965), vesicle (GO:0031982), azurophil granule membrane (GO:0035577), nucleus (GO:0005634), membrane (GO:0016020), perinuclear region of cytoplasm (GO:0048471), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Sphingolipid metabolism	1
Innate Immune System	1
Protein localization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	4
lipid transport	3
cellular anatomical structure	3
protein dimerization activity	2
intracellular membrane-bounded organelle	2
organelle membrane	2
sphingomyelin metabolic process	1
phospholipid biosynthetic process	1
sphingolipid biosynthetic process	1
intercellular transport	1
intracellular transport	1
Golgi vesicle transport	1
organophosphate ester transport	1
organic hydroxy compound transport	1
viral process	1
viral life cycle	1
exit from host cell	1
sterol transport	1
neuron development	1
plasma membrane bounded cell projection organization	1
nitrogen compound transport	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
viral genome replication	1
host-mediated perturbation of viral process	1
host-mediated activation of viral process	1
host-mediated perturbation of viral genome replication	1
membrane organization	1
protein localization to organelle	1
endoplasmic reticulum to Golgi vesicle-mediated transport	1
vesicle budding from membrane	1
tubulin binding	1
protein binding	1
protein domain specific binding	1
identical protein binding	1
protein-macromolecule adaptor activity	1
cell adhesion molecule binding	1
binding	1
Golgi apparatus	1

Protein interactions and networks

STRING

2872 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VAPA	OSBP	P22059	998
VAPA	ACBD5	Q5T8D3	987
VAPA	CERT1	Q9Y5P4	980
VAPA	STARD3	Q14849	945
VAPA	OSBPL9	Q96SU4	913
VAPA	ACBD4	Q8NC06	870
VAPA	STARD3NL	O95772	864
VAPA	KCNB1	Q14721	847
VAPA	IFITM3	Q01628	838
VAPA	ZFYVE27	Q5T4F4	818
VAPA	SNX2	P82862	814
VAPA	OSBP2	Q969R2	788
VAPA	VAMP8	Q9BV40	766
VAPA	OSBPL5	Q9H0X9	760
VAPA	KCNB2	Q92953	749

IntAct

437 interactions, top by confidence:

A	B	Type	Score
OSBP	VAPA	psi-mi:“MI:0915”(physical association)	0.890
OSBP	VAPA	psi-mi:“MI:2364”(proximity)	0.890
RMDN2	VAPA	psi-mi:“MI:0915”(physical association)	0.800
OSBPL9	VAPB	psi-mi:“MI:0914”(association)	0.790
OSBPL1A	VAPB	psi-mi:“MI:0914”(association)	0.760
USP20	VAPA	psi-mi:“MI:0915”(physical association)	0.740
APOD	VAPA	psi-mi:“MI:0915”(physical association)	0.720
EGFR	VAPA	psi-mi:“MI:0915”(physical association)	0.710
OSBPL1A	VAPA	psi-mi:“MI:0407”(direct interaction)	0.700
VAPA	OPRM1	psi-mi:“MI:0915”(physical association)	0.680
PGRMC2	VAPA	psi-mi:“MI:0915”(physical association)	0.670
OSBPL2	VAPA	psi-mi:“MI:0915”(physical association)	0.660
RSAD2	VAPA	psi-mi:“MI:2364”(proximity)	0.660
RSAD2	VAPA	psi-mi:“MI:0403”(colocalization)	0.660
RSAD2	VAPA	psi-mi:“MI:0915”(physical association)	0.660
VAPA	RSAD2	psi-mi:“MI:0403”(colocalization)	0.660
VAPA	RSAD2	psi-mi:“MI:0914”(association)	0.660
RAB8A	WDR91	psi-mi:“MI:0914”(association)	0.600
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
	VAPA	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (1077): VAPA (Affinity Capture-MS), VAPA (Two-hybrid), VAPA (Two-hybrid), ZBTB22 (Two-hybrid), GPR128 (Two-hybrid), VAPA (Two-hybrid), VAPA (Affinity Capture-Western), VAPA (Affinity Capture-Western), VAPA (Affinity Capture-Western), VAPA (Affinity Capture-MS), VAPA (Affinity Capture-MS), VAPA (Affinity Capture-MS), VAPA (Affinity Capture-MS), VAPA (Affinity Capture-MS), VAPA (Affinity Capture-MS)

ESM2 similar proteins: A1A4P5, A1DGS2, A2R7Z2, B0BN18, O04350, O35685, O70591, O75347, O76031, P48427, P48428, P50502, P50503, P80584, Q07866, Q08851, Q08DB5, Q0VCY1, Q13190, Q15691, Q17QG2, Q3ZBD9, Q4SPU8, Q5D016, Q5R581, Q5R601, Q5R7N3, Q5R7Z5, Q5RF31, Q5U2U0, Q5ZLC7, Q5ZLF0, Q61166, Q63525, Q66HR2, Q66T82, Q68FJ8, Q6P848, Q6V291, Q8K1E0

Diamond homologs: A2VDZ9, A5GFS8, O60119, O82213, O95292, P40075, Q0VCY1, Q10484, Q16943, Q5R601, Q6Q595, Q84WW5, Q8NHP6, Q8VZ95, Q9LVU1, Q9P0L0, Q9QY76, Q9SHC8, Q9SYC9, Q9WV55, Q9Z269, Q9Z270, B9DHD7, Q9CWP6, Q8VYN2, Q1ECE0, P53021, P53023, A0A290U7C4, C4B7M7, F4HT77, F4JNA9, F4JNB7, F4JT78, F4JT80, F4JWM0, F4KHH8, F4KHI3, F4KIF3, O23530

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
KCNB1	“up-regulates quantity”	VAPA	relocalization
KCNB2	“up-regulates quantity”	VAPA	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	34
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
4683119	NM_194434.3(VAPA):c.34G>T (p.Glu12Ter)	Likely pathogenic

SpliceAI

2206 predictions. Top by Δscore:

Variant	Effect	Δscore
18:9914332:AAAGG:A	donor_loss	1.0000
18:9914333:AAGGT:A	donor_loss	1.0000
18:9914334:AGG:A	donor_loss	1.0000
18:9914337:T:A	donor_loss	1.0000
18:9931958:TTCAG:T	donor_loss	1.0000
18:9931959:TCAGG:T	donor_loss	1.0000
18:9931960:CAG:C	donor_loss	1.0000
18:9931961:AGG:A	donor_loss	1.0000
18:9931962:GGT:G	donor_loss	1.0000
18:9931963:G:T	donor_loss	1.0000
18:9931964:T:C	donor_loss	1.0000
18:9936104:A:AG	acceptor_gain	1.0000
18:9936105:T:G	acceptor_gain	1.0000
18:9936108:A:AG	acceptor_gain	1.0000
18:9936108:A:G	acceptor_loss	1.0000
18:9936109:G:GG	acceptor_gain	1.0000
18:9936109:GT:G	acceptor_gain	1.0000
18:9936109:GTA:G	acceptor_gain	1.0000
18:9936109:GTAA:G	acceptor_gain	1.0000
18:9936109:GTAAT:G	acceptor_gain	1.0000
18:9936209:CTGTG:C	donor_gain	1.0000
18:9936211:GTG:G	donor_gain	1.0000
18:9936212:TG:T	donor_gain	1.0000
18:9936213:GG:G	donor_gain	1.0000
18:9936214:G:GA	donor_loss	1.0000
18:9936214:G:GG	donor_gain	1.0000
18:9936215:T:TC	donor_loss	1.0000
18:9936984:A:AG	acceptor_gain	1.0000
18:9936984:AGT:A	acceptor_gain	1.0000
18:9936984:AGTG:A	acceptor_gain	1.0000

AlphaMissense

1644 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:9914300:T:A	L15Q	1.000
18:9914300:T:C	L15P	1.000
18:9914306:T:A	L17H	1.000
18:9914324:T:A	L23H	1.000
18:9914324:T:C	L23P	1.000
18:9914329:T:A	F25I	1.000
18:9914329:T:C	F25L	1.000
18:9914329:T:G	F25V	1.000
18:9914330:T:C	F25S	1.000
18:9914330:T:G	F25C	1.000
18:9914331:C:A	F25L	1.000
18:9914331:C:G	F25L	1.000
18:9914335:G:C	G27R	1.000
18:9914335:G:T	G27C	1.000
18:9931810:G:A	G27D	1.000
18:9931815:T:A	F29I	1.000
18:9931815:T:C	F29L	1.000
18:9931815:T:G	F29V	1.000
18:9931816:T:C	F29S	1.000
18:9931816:T:G	F29C	1.000
18:9931817:C:A	F29L	1.000
18:9931817:C:G	F29L	1.000
18:9931828:T:A	V33D	1.000
18:9931840:T:A	L37H	1.000
18:9931840:T:C	L37P	1.000
18:9931840:T:G	L37R	1.000
18:9931846:T:C	L39S	1.000
18:9931846:T:G	L39W	1.000
18:9931851:A:G	N41D	1.000
18:9931853:T:A	N41K	1.000

dbSNP variants (sampled 300 via entrez): RS1000003007 (18:9922389 C>A), RS1000026677 (18:9960359 C>T), RS1000030035 (18:9937328 T>C), RS1000066664 (18:9954841 G>C), RS1000097626 (18:9955152 A>G), RS1000164801 (18:9953737 T>C), RS1000250357 (18:9949481 G>A), RS1000356578 (18:9942659 A>G,T), RS1000388094 (18:9949739 A>T), RS1000404041 (18:9956525 G>A), RS1000446907 (18:9951673 G>C), RS1000449308 (18:9921325 G>GT), RS1000471164 (18:9923954 C>T), RS1000509984 (18:9919345 T>A), RS1000521121 (18:9940552 T>C)

Disease associations

OMIM: gene MIM:605703 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): microcephaly (MONDO:0001149)

Orphanet (0):

HPO phenotypes

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

HPO	Term
HP:0000252	Microcephaly

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST001784_15	Pulmonary function (smoking interaction)	3.000000e-07
GCST001784_37	Pulmonary function (smoking interaction)	4.000000e-07
GCST006479_18	Diverticular disease	8.000000e-06
GCST006979_261	Heel bone mineral density	2.000000e-12
GCST007430_63	Peak expiratory flow	4.000000e-24
GCST007431_60	Lung function (FEV1/FVC)	2.000000e-18
GCST007432_95	FEV1	4.000000e-10
GCST009391_1113	Metabolite levels	9.000000e-06

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0003892	pulmonary function measurement
EFO:0004713	FEV/FVC ratio
EFO:0009959	diverticular disease
EFO:0009270	heel bone mineral density
EFO:0009718	peak expiratory flow
EFO:0004314	forced expiratory volume
EFO:0010448	3-hydroxyphenylacetic acid measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066429 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.36	Kd	435.1	nM	CHEMBL5653589
6.36	ED50	435.1	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149753: Binding affinity to human VAPA incubated for 45 mins by Kinobead based pull down assay	kd	0.4351	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, decreases methylation, decreases expression, increases expression	4
bisphenol S	affects expression, affects cotreatment, decreases methylation, increases expression	3
bisphenol F	increases expression, affects cotreatment	2
sodium arsenite	decreases expression, increases reaction, increases expression	2
entinostat	decreases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Arsenic	affects cotreatment, affects expression, affects methylation	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Valproic Acid	decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
FR900359	decreases phosphorylation	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
glycidyl methacrylate	increases expression	1
lead acetate	decreases expression, increases reaction	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
arsenite	affects binding, increases reaction	1
tetrabromobisphenol A	decreases expression	1
coumarin	affects phosphorylation	1
hydroquinone	decreases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
jinfukang	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652795	Binding	Binding affinity to human VAPA incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A9BN	DG6-VAP33-GFP	Cancer cell line
CVCL_TX27	HAP1 VAPA (-) 1	Cancer cell line	Male
CVCL_TX28	HAP1 VAPA (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.