VAPB

Summary

VAPB (VAMP associated protein B and C, HGNC:12649) is a protein-coding gene on chromosome 20q13.32, encoding Vesicle-associated membrane protein-associated protein B/C (O95292). 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 found in plasma and intracellular vesicle membranes. The encoded protein is found as a homodimer and as a heterodimer with VAPA. This protein also can interact with VAMP1 and VAMP2 and may be involved in vesicle trafficking.

Source: NCBI Gene 9217 — RefSeq curated summary.

At a glance

• Gene–disease (curated): amyotrophic lateral sclerosis type 8 (Definitive, ClinGen) — +2 more curated relationships
• Clinical variants (ClinVar): 409 total — 2 pathogenic
• Phenotypes (HPO): 75
• Druggable target: yes
• MANE Select transcript: NM_004738

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12649
Approved symbol	VAPB
Name	VAMP associated protein B and C
Location	20q13.32
Locus type	gene with protein product
Status	Approved
Aliases	VAP-B, VAP-C, ALS8
Ensembl gene	ENSG00000124164
Ensembl biotype	protein_coding
OMIM	605704
Entrez	9217

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 7 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000265619, ENST00000395802, ENST00000463370, ENST00000475243, ENST00000476395, ENST00000520497, ENST00000903508, ENST00000903509, ENST00000903510, ENST00000915806, ENST00000946349

RefSeq mRNA: 2 — MANE Select: NM_004738 NM_001195677, NM_004738

CCDS: CCDS33498, CCDS56198

Canonical transcript exons

ENST00000475243 — 6 exons

Exon	Start	End
ENSE00000845810	58389229	58389517
ENSE00001876198	58444077	58451101
ENSE00003497704	58434602	58434705
ENSE00003546608	58418211	58418363
ENSE00003576198	58438945	58439025
ENSE00003628481	58440907	58441083

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 98.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 40.0240 / max 258.3651, expressed in 1815 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
185501	36.1875	1813
185499	1.7458	908
185500	1.2383	615
185498	0.8523	459

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	98.23	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.08	gold quality
middle temporal gyrus	UBERON:0002771	98.03	gold quality
endometrium epithelium	UBERON:0004811	96.06	gold quality
postcentral gyrus	UBERON:0002581	95.40	gold quality
parietal lobe	UBERON:0001872	95.00	gold quality
pons	UBERON:0000988	94.74	gold quality
superior frontal gyrus	UBERON:0002661	94.64	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	94.47	gold quality
entorhinal cortex	UBERON:0002728	94.19	gold quality
secondary oocyte	CL:0000655	94.15	gold quality
biceps brachii	UBERON:0001507	93.95	gold quality
deltoid	UBERON:0001476	93.84	gold quality
islet of Langerhans	UBERON:0000006	93.76	gold quality
superior vestibular nucleus	UBERON:0007227	93.63	gold quality
substantia nigra pars compacta	UBERON:0001965	93.41	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.41	gold quality
tibialis anterior	UBERON:0001385	93.37	gold quality
primary visual cortex	UBERON:0002436	93.33	gold quality
parotid gland	UBERON:0001831	93.29	gold quality
left ventricle myocardium	UBERON:0006566	93.28	gold quality
medulla oblongata	UBERON:0001896	93.11	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.09	gold quality
adrenal cortex	UBERON:0001235	93.07	gold quality
skeletal muscle tissue	UBERON:0001134	93.01	gold quality
muscle of leg	UBERON:0001383	92.97	gold quality
gastrocnemius	UBERON:0001388	92.95	gold quality
left adrenal gland cortex	UBERON:0035825	92.94	gold quality
right adrenal gland cortex	UBERON:0035827	92.91	gold quality
right adrenal gland	UBERON:0001233	92.90	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.85
E-MTAB-6058	no	72.78

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EHMT2, GATA3

miRNA regulators (miRDB)

330 targeting VAPB, 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-6867-5P	100.00	82.21	3464
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-548AN	99.97	70.91	2817

Literature-anchored findings (GeneRIF, showing 40)

• evidence that Nir (Nir1, Nir2, and Nir3)-VAP-B interactions are mediated through the conserved FFAT (two phenylalanines (FF) in acidic tract) motif present in Nir proteins (PMID:15545272)
• Regulation of ceramide transport protein by oxyste rbinding proteins, sterols, and VAMP reveals a novel mechanism for integrating sterol regulatory signals with ceramide transport and sphingomyelin synthesis in the Golgi apparatus. (PMID:16571669)
• Frequency of the detected exon variation in the VAPB gene was not significantly different between patients and controls. VAPB mutations are not a common cause of adult-onset sporadic amyotrophic lateral sclerosis. (PMID:16729899)
• Overexpression of wild type VAPB promotes unfolded protein response, which is a reaction of the endoplasmic reticulum to suppress accumulation of misfolded proteins. (PMID:16891305)
• it is suggested that VAPB mutations do not significantly contribute to the genetic causes of sporadic amyotrophic lateral sclerosis in the UK and Northern Europe (PMID:17536055)
• P56S mutation in VAP-B may lead to a less stable interaction of this endoplasmic reticulum protein with at least two other proteins: tubulin and GAPDH. (PMID:17540579)
• VAPB is abundant in motor neurons and the P56S substitution causes aggregation of mutant VAPB in immobile tubular ER clusters, perturbs FFAT-motif binding, and traps endogenous VAP in mutant aggregates, which may cause motor neuron degeneration. (PMID:17804640)
• DVAP-33A and hVAPB are functionally interchangeable and transgenic expression of mutant DVAP-33A in neurons recapitulates major hallmarks of the human diseases including locomotion defects, neuronal death and aggregate formation. (PMID:17947296)
• Mutations in the VAPB gene are rare and the Delta S160 variant does not contribute to the development of amyotrophic lateral sclerosis. (PMID:18322265)
• Study shows that the MSP domains of VAP protein, VAPB are cleaved and secreted ligands for Eph receptors (PMID:18555774)
• These findings are indistinguishable from those of other motor neuron disorders, although the predominant involvement of the proximal limbs and of the abdominal muscles may be of some help in the appropriate clinical setting. (PMID:18677189)
• VAPB mRNA levels were decreased in the spinal cord of ALS patients compared to controls and Expression of VAPB mRNA and protein was predominantly localised to large motor neurones. (PMID:18701194)
• 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)
• Using shotgun mass spectrometry, we found this protein differentially expressed in the dorsolateral prefrontal cortex from patients with schizophrenia (PMID:19165527)
• Overexpression of VAP-C impaired the RNA replication of the HCV replicon, whereas overexpression of VAP-A and VAP-B enhanced the replication. (PMID:19515777)
• these results demonstrate that the amyotrophic lateral sclerosis -linked VAPB mutant causes dramatic ER restructuring that may underlie its pathogenicity in motoneurons. (PMID:20008544)
• the mechanism by which VAP-B(P56S) aggregates are formed and induce familial motor neuron diseases (PMID:20207736)
• under conditions of proteasomal inhibition, as encountered in many neurodegenerative diseases including ALS, variant VAPB proteins might accumulate in affected cells and contribute to ALS pathogenesis. (PMID:20227395)
• Pro56Ser mutation of VAPB lead to amyotrophic lateral sclerosis by eliminating the native protein structure. (PMID:20377183)
• study reports the first identification of the p.P56S mutation in the VAPB gene in a non-Brazilian patient (PMID:20447143)
• Adeno-associated viral-mediated over-expression of both wild-type and mutated form of human VAPB selectively induces death of primary mouse motor neurons, albeit with different kinetics. (PMID:20477942)
• Mutations in SOD1, ANG, VAPB, TARDBP and FUS genes have been identified in amyotrophic lateral sclerosis. (PMID:20577002)
• newly identified mutation in human FALS has a pathogenic effect, supporting and reinforcing the role of VAPB as a causative gene of ALS. (PMID:20940299)
• 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)
• VAPB protein levels are reduced in motor neurons derived form induced pluripotent stem cells of amyotrophic lateral sclerosis patients. (PMID:21685205)
• endoplasmic reticulum stress and corruption of the proteasome function might contribute to the aberrant protein homeostasis associated with hVAPB (PMID:21998752)
• T46I mutant of the hVAPB MSP domain is associated with amyotrophic lateral sclerosis. (PMID:22069488)
• Loss of either VAPB or PTPIP51 perturbs uptake of Calcium by mitochondria and results in amyotrophic lateral sclerosis. (PMID:22131369)
• ALS mutant VAPBP56S perturbs anterograde mitochondrial axonal transport by disrupting Ca(2+) homeostasis and effecting the Miro1/kinesin-1 interaction with tubulin. (PMID:22258555)
• The mutation in VAPB that causes amyotrophic lateral sclerosis also causes the block of transport of nucleoporins and emerin to the nuclear envelope. (PMID:22454507)
• Transfection of a dominant-negative form of the AAA ATPase p97/VCP stabilizes mutant VAPB, suggesting a role for this ATPase in extracting the aggregated protein from the inclusions. (PMID:22611258)
• The binding residues have been successfully mapped out on both NS5A and VAPB, thus allowing the construct of the complex structure. (PMID:22720086)
• structual basis of VAPC binding to HCV NS5B (PMID:22815741)
• This study screened a cohort of 755 sporadic ALS patients, 111 familial ALS patients (97 families), and 765 control subjects of Dutch descent for mutations in vesicle-associated membrane protein B (VAPB). (PMID:22878164)
• VAPB promotes breast tumor growth by modulation of Akt activity. (PMID:23049696)
• These results suggest that changes in wild type VAPB do not play a significant role in amyotrophic lateral sclerosis cases that are not caused by VAPB mutations (PMID:23281774)
• this discovery provides a mechanism for ALS-causing VAPB mutants/variants to gain novel functions such as to mediate ER structure before significant accumulation of aggregates occurs. (PMID:23333387)
• Partial or complete loss of VAPB function leads to motor deficit but is unable to trigger a full-blown amyotrophic lateral sclerosis phenotype. (PMID:23446633)
• Findings provide new pathophysiological mechanisms of P56S VAPB that differentially affect the function and survival of corticospinal and spinal motor neurons in familial amyotrophic lateral sclerosis 8. (PMID:23771029)
• In patients with familial or sporadic amyotrophic lateral sclerosis (ALS) from Portugal, Iceland and Sweden no association is found with disease and VAMP-associated protein type B (VAPB) mutations. (PMID:23971766)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	vapb	ENSDARG00000070435
mus_musculus	Vapb	ENSMUSG00000054455
rattus_norvegicus	Vapb	ENSRNOG00000005331
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): VAPA (ENSG00000101558)

Protein

Protein identifiers

Vesicle-associated membrane protein-associated protein B/C — O95292 (reviewed: O95292)

All UniProt accessions (3): E5RK64, O95292, Q53XM7

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. Interacts with STARD3 in a FFAT motif phosphorylation dependent manner. Via interaction with WDR44 participates in neosynthesized protein export. Participates in the endoplasmic reticulum unfolded protein response (UPR) by inducing ERN1/IRE1 activity. Involved in cellular calcium homeostasis regulation.

Subunit / interactions. Homodimer, and heterodimer with VAPA. Interacts with VAMP1 and VAMP2. Interacts (via MSP domain) with ZFYVE27. Interacts with RMDN3. Interacts with KIF5A in a ZFYVE27-dependent manner. Interacts (via MSP domain) with STARD3 (via phospho-FFAT motif). 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), OSBPL1A (via FFAT motif), KCNB1 (via phosphorylated FFAT motif) and KCNB2 (via phosphorylated FFAT motif). Interacts (via MSP domain) with WDR44 (via FFAT motif); the interactions connect the endoplasmic reticulum (ER) with the endosomal tubule. (Microbial infection) Interacts (via MSP domain) with hepatitis C virus (HCV) non-structural protein 5A (via disordered domain D3). Interacts with HCV RNA-directed RNA polymerase.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Ubiquitous. Isoform 1 predominates.

Disease relevance. Amyotrophic lateral sclerosis 8 (ALS8) [MIM:608627] A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. The disease is caused by variants affecting the gene represented in this entry. Spinal muscular atrophy, proximal, adult, autosomal dominant (SMAPAD) [MIM:182980] A form of spinal muscular atrophy, a neuromuscular disorder characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. SMAPAD is characterized by proximal muscle weakness that begins in the lower limbs and then progresses to upper limbs, onset in late adulthood (after third decade) and a benign course. Most of the patients remain ambulatory 10 to 40 years after clinical onset. The disease is caused by variants affecting the gene represented in this entry.

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?
O95292-1	1, VAP-B	yes
O95292-2	2, VAP-C

RefSeq proteins (2): NP_001182606, NP_004729* (*=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 (40 total): strand 9, modified residue 8, sequence conflict 4, turn 4, mutagenesis site 3, splice variant 2, sequence variant 2, initiator methionine 1, chain 1, cross-link 1, topological domain 1, transmembrane region 1, domain 1, coiled-coil region 1, site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3IKK	X-RAY DIFFRACTION	2.5
2MDK	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95292-F1	77.45	0.40

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

Post-translational modifications (9): 156, 158, 159, 160, 206, 147, 2, 146, 150

Mutagenesis-validated functional residues (3):

Position	Phenotype
43	does not affect interaction with the conventional ffat motif of osbpl1a. impairs the interactions of the msp domain with
87	prevents binding to the ffat motif in target proteins; when associated with d-89.
89	prevents binding to the ffat motif in target proteins; when associated with d-87.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-1660661	Sphingolipid de novo biosynthesis
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9013106	RHOC GTPase cycle
R-HSA-9013404	RAC2 GTPase cycle
R-HSA-9013405	RHOD GTPase cycle
R-HSA-9013408	RHOG GTPase cycle

MSigDB gene sets: 383 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, GGGACCA_MIR133A_MIR133B, GOBP_IRE1_MEDIATED_UNFOLDED_PROTEIN_RESPONSE, TGCGCANK_UNKNOWN, KAAB_FAILED_HEART_ATRIUM_DN, GOBP_VESICLE_ORGANIZATION, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_REGULATION_BY_VIRUS_OF_VIRAL_PROTEIN_LEVELS_IN_HOST_CELL, GOBP_NEGATIVE_REGULATION_OF_VIRAL_PROCESS, GOBP_POSITIVE_REGULATION_OF_VIRAL_GENOME_REPLICATION, MCBRYAN_PUBERTAL_TGFB1_TARGETS_DN, GOBP_MODULATION_OF_PROCESS_OF_ANOTHER_ORGANISM, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_HOST_MEDIATED_PERTURBATION_OF_VIRAL_PROCESS, GOBP_CELLULAR_RESPONSE_TO_TOPOLOGICALLY_INCORRECT_PROTEIN

GO Biological Process (17): intracellular calcium ion homeostasis (GO:0006874), endoplasmic reticulum to Golgi vesicle-mediated transport (GO:0006888), endoplasmic reticulum organization (GO:0007029), viral release from host cell (GO:0019076), cholesterol transport (GO:0030301), endoplasmic reticulum unfolded protein response (GO:0030968), IRE1-mediated unfolded protein response (GO:0036498), suppression of viral release by host (GO:0044790), host-mediated suppression of viral genome replication (GO:0044828), host-mediated activation of viral genome replication (GO:0044829), host-mediated perturbation of viral RNA genome replication (GO:0044830), positive regulation of viral genome replication (GO:0045070), negative regulation by virus of viral protein levels in host cell (GO:0046725), obsolete endoplasmic reticulum-plasma membrane tethering (GO:0061817), COPII-coated vesicle budding (GO:0090114), endoplasmic reticulum membrane organization (GO:0090158), response to unfolded protein (GO:0006986)

GO Molecular Function (9): microtubule binding (GO:0008017), enzyme binding (GO:0019899), 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), beta-tubulin binding (GO:0048487), protein binding (GO:0005515)

GO Cellular Component (9): cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), presynapse (GO:0098793), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
RHO GTPase cycle	5
Sphingolipid metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	3
synapse	3
viral genome replication	2
host-mediated perturbation of viral process	2
tubulin binding	2
protein dimerization activity	2
endomembrane system	2
intracellular membrane-bounded organelle	2
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
intercellular transport	1
intracellular transport	1
Golgi vesicle transport	1
organelle organization	1
endomembrane system organization	1
viral process	1
viral life cycle	1
exit from host cell	1
sterol transport	1
cellular response to unfolded protein	1
response to endoplasmic reticulum stress	1
intracellular signal transduction	1
endoplasmic reticulum unfolded protein response	1
defense response to virus	1
host-mediated activation of viral process	1
host-mediated perturbation of viral genome replication	1
viral RNA genome replication	1
regulation of viral genome replication	1
positive regulation of viral process	1
regulation by virus of viral protein levels in host cell	1
negative regulation of viral process	1
endoplasmic reticulum to Golgi vesicle-mediated transport	1
vesicle budding from membrane	1
endoplasmic reticulum organization	1
membrane organization	1
response to topologically incorrect protein	1
protein binding	1
protein domain specific binding	1
identical protein binding	1

Protein interactions and networks

STRING

2602 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VAPB	RMDN3	Q96TC7	997
VAPB	ACBD5	Q5T8D3	991
VAPB	ACBD4	Q8NC06	958
VAPB	ATF6	P18850	895
VAPB	TARDBP	Q13148	884
VAPB	ALS2	Q96Q42	878
VAPB	SETX	Q7Z333	861
VAPB	CERT1	Q9Y5P4	856
VAPB	MFN2	O95140	856
VAPB	FIG4	Q92562	843
VAPB	SOD1	P00441	842
VAPB	FUS	P35637	835
VAPB	OSBPL9	Q96SU4	830
VAPB	OSBP	P22059	822
VAPB	SNX2	P82862	808

IntAct

341 interactions, top by confidence:

A	B	Type	Score
USP20	VAPB	psi-mi:“MI:0915”(physical association)	0.850
VAPB	RMDN2	psi-mi:“MI:0915”(physical association)	0.840
OSBPL9	VAPB	psi-mi:“MI:0914”(association)	0.790
OSBPL1A	VAPB	psi-mi:“MI:0914”(association)	0.760
OSBPL1A	VAPB	psi-mi:“MI:0407”(direct interaction)	0.760
VAPB	TTC39B	psi-mi:“MI:0915”(physical association)	0.740
VAPB	FAM83G	psi-mi:“MI:0914”(association)	0.730
PRKACA	VAPB	psi-mi:“MI:0914”(association)	0.730
EMD	VAPB	psi-mi:“MI:0915”(physical association)	0.670
OSBPL2	VAPB	psi-mi:“MI:0915”(physical association)	0.660
TMEM252	VAPB	psi-mi:“MI:0915”(physical association)	0.560
VAPB	HSD17B13	psi-mi:“MI:0915”(physical association)	0.560
VAPB	CYBRD1	psi-mi:“MI:0915”(physical association)	0.560
VAPB	CYB561	psi-mi:“MI:0915”(physical association)	0.560
VAPB	TMEM252	psi-mi:“MI:0915”(physical association)	0.560
GPR25	VAPB	psi-mi:“MI:0915”(physical association)	0.560
ZBTB22	VAPB	psi-mi:“MI:0915”(physical association)	0.560
	VAPB	psi-mi:“MI:0915”(physical association)	0.560
VAPB	JAGN1	psi-mi:“MI:0915”(physical association)	0.560
VAPB	SLC35C2	psi-mi:“MI:0915”(physical association)	0.560
VAPB	AIG1	psi-mi:“MI:0915”(physical association)	0.560
VAPB	FAM174A	psi-mi:“MI:0915”(physical association)	0.560
VAPB	RETREG3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (864): VAPB (Two-hybrid), OSBPL2 (Two-hybrid), USP20 (Two-hybrid), RMDN2 (Two-hybrid), VAPB (Affinity Capture-MS), VAPB (Affinity Capture-MS), VAPB (Affinity Capture-MS), VAPB (Affinity Capture-MS), VAPB (Affinity Capture-MS), VAPB (Affinity Capture-MS), VAPB (Affinity Capture-MS), VAPB (Affinity Capture-MS), RAB3GAP2 (Affinity Capture-MS), PITPNM1 (Affinity Capture-MS), TTC39B (Affinity Capture-MS)

ESM2 similar proteins: A0A8C0TYJ0, A2AWA9, A2VDZ9, A5GFS8, O70133, O76031, O88506, O95292, O95747, Q08E27, Q0VCY1, Q12959, Q13330, Q15691, Q16514, Q3T174, Q3ZBD9, Q5PYH5, Q5R495, Q5R601, Q5R6Y5, Q5R7N3, Q5R7Z5, Q5U2U0, Q5ZHN3, Q5ZIL4, Q61166, Q61187, Q62599, Q62696, Q66HR2, Q68FK8, Q6AY57, Q6IRE4, Q6ZVM7, Q7ZWU5, Q80W47, Q811D0, Q863I2, Q8K4B0

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

3 interactions.

A	Effect	B	Mechanism
KCNB1	“up-regulates quantity”	VAPB	relocalization
KCNB2	“up-regulates quantity”	VAPB	relocalization
VAPB	“form complex”	“VAPB-PTPIP51 complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 143 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
Signaling by ERBB2 ECD mutants	5	37.7×	6e-05
GRB2 events in ERBB2 signaling	5	35.6×	6e-05
CD209 (DC-SIGN) signaling	5	29.2×	7e-05
SHC1 events in ERBB2 signaling	5	26.7×	7e-05
Signaling by ERBB2 TMD/JMD mutants	5	26.7×	7e-05
Signaling by ERBB2 KD Mutants	5	23.8×	1e-04
EPH-Ephrin signaling	5	9.3×	3e-03
Leishmania infection	5	9.2×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	230
Likely benign	93
Benign	51

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
30510	NM_004738.5(VAPB):c.137C>T (p.Thr46Ile)	Pathogenic
4806	NM_004738.5(VAPB):c.166C>T (p.Pro56Ser)	Pathogenic

SpliceAI

1486 predictions. Top by Δscore:

Variant	Effect	Δscore
20:58389515:GAGGT:G	donor_loss	1.0000
20:58389516:AGGT:A	donor_loss	1.0000
20:58389517:GGTA:G	donor_loss	1.0000
20:58389518:G:GA	donor_loss	1.0000
20:58389519:T:A	donor_loss	1.0000
20:58418205:CTACA:C	acceptor_loss	1.0000
20:58418206:TACA:T	acceptor_loss	1.0000
20:58418208:CA:C	acceptor_loss	1.0000
20:58418209:AGG:A	acceptor_loss	1.0000
20:58418210:G:A	acceptor_loss	1.0000
20:58418361:CTGGT:C	donor_loss	1.0000
20:58418362:TGGT:T	donor_loss	1.0000
20:58418363:GGTAA:G	donor_loss	1.0000
20:58418364:G:T	donor_loss	1.0000
20:58418365:TAA:T	donor_loss	1.0000
20:58434701:CAGTA:C	donor_gain	1.0000
20:58434703:GTA:G	donor_gain	1.0000
20:58434704:TA:T	donor_gain	1.0000
20:58434706:G:GG	donor_gain	1.0000
20:58438943:A:AG	acceptor_gain	1.0000
20:58438944:G:GG	acceptor_gain	1.0000
20:58440905:A:AG	acceptor_gain	1.0000
20:58440906:G:GG	acceptor_gain	1.0000
20:58440906:GC:G	acceptor_gain	1.0000
20:58440906:GCAT:G	acceptor_gain	1.0000
20:58444152:G:GT	donor_gain	1.0000
20:58389515:GAG:G	donor_gain	0.9900
20:58418209:A:AG	acceptor_gain	0.9900
20:58418210:G:GG	acceptor_gain	0.9900
20:58418364:G:GG	donor_gain	0.9900

AlphaMissense

1607 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:58389506:T:A	L16H	1.000
20:58389506:T:C	L16P	1.000
20:58389511:T:C	F18L	1.000
20:58389511:T:G	F18V	1.000
20:58389512:T:C	F18S	1.000
20:58389512:T:G	F18C	1.000
20:58389513:C:A	F18L	1.000
20:58389513:C:G	F18L	1.000
20:58418216:T:C	F22L	1.000
20:58418217:T:C	F22S	1.000
20:58418218:C:A	F22L	1.000
20:58418218:C:G	F22L	1.000
20:58418241:T:A	L30Q	1.000
20:58418241:T:C	L30P	1.000
20:58418247:T:A	L32H	1.000
20:58418247:T:C	L32P	1.000
20:58418252:A:G	N34D	1.000
20:58418254:C:A	N34K	1.000
20:58418254:C:G	N34K	1.000
20:58418271:T:A	V40E	1.000
20:58418276:T:C	F42L	1.000
20:58418277:T:C	F42S	1.000
20:58418278:T:A	F42L	1.000
20:58418278:T:G	F42L	1.000
20:58418279:A:G	K43E	1.000
20:58418281:G:C	K43N	1.000
20:58418281:G:T	K43N	1.000
20:58418283:T:A	V44E	1.000
20:58418283:T:C	V44A	1.000
20:58418285:A:C	K45Q	1.000

dbSNP variants (sampled 300 via entrez): RS1000114730 (20:58435497 G>A), RS1000201597 (20:58388376 T>A,C), RS1000203775 (20:58417320 T>C), RS1000267766 (20:58428644 A>G), RS1000321875 (20:58417046 C>G), RS1000335656 (20:58388673 T>C), RS1000351743 (20:58423391 A>C,T), RS1000447154 (20:58423446 A>G), RS1000449846 (20:58434030 G>A), RS1000515438 (20:58415667 C>T), RS1000522203 (20:58392476 T>G), RS1000591867 (20:58393827 G>A), RS1000621180 (20:58421790 G>A), RS1000646657 (20:58409984 G>A), RS1000671855 (20:58387245 G>T)

Disease associations

OMIM: gene MIM:605704 | disease phenotypes: MIM:182980, MIM:608627

GenCC curated gene-disease

Disease	Classification	Inheritance
amyotrophic lateral sclerosis type 8	Strong	Autosomal dominant
adult-onset proximal spinal muscular atrophy, autosomal dominant	Supportive	Autosomal dominant
amyotrophic lateral sclerosis	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
amyotrophic lateral sclerosis type 8	Definitive	AD

Mondo (3): adult-onset proximal spinal muscular atrophy, autosomal dominant (MONDO:0008453), amyotrophic lateral sclerosis type 8 (MONDO:0012077), amyotrophic lateral sclerosis (MONDO:0004976)

Orphanet (2): Autosomal dominant adult-onset proximal spinal muscular atrophy (Orphanet:209335), Amyotrophic lateral sclerosis (Orphanet:803)

HPO phenotypes

75 total (30 of 75 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000217	Xerostomia
HP:0000708	Atypical behavior
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000739	Anxiety
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001265	Hyporeflexia
HP:0001284	Areflexia
HP:0001308	Tongue fasciculations
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0001387	Joint stiffness
HP:0001618	Dysphonia
HP:0001824	Weight loss
HP:0001883	Talipes
HP:0002015	Dysphagia
HP:0002062	Abnormal pyramidal tract morphology
HP:0002094	Dyspnea
HP:0002145	Frontotemporal dementia
HP:0002174	Postural tremor
HP:0002180	Neurodegeneration
HP:0002307	Drooling
HP:0002313	Spastic paraparesis
HP:0002360	Sleep disturbance
HP:0002362	Shuffling gait
HP:0002380	Fasciculations
HP:0002460	Distal muscle weakness
HP:0002463	Language impairment

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
C563895	Amyotrophic Lateral Sclerosis 8 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066990 (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
8.26	Kd	5.509	nM	CHEMBL5653589
8.26	ED50	5.509	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	2149754: Binding affinity to human VAPB incubated for 45 mins by Kinobead based pull down assay	kd	0.0055	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression	3
sodium arsenite	increases abundance, increases expression, affects binding, increases reaction, affects cotreatment (+1 more)	3
bisphenol A	increases expression	2
deguelin	decreases expression	2
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	decreases expression	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
Antimycin A	decreases expression	2
Rotenone	decreases expression	2
FR900359	decreases phosphorylation	1
geldanamycin	increases expression	1
methylmercuric chloride	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	increases expression	1
beta-lapachone	increases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
coumarin	increases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
fenpyroximate	decreases expression	1
pyrimidifen	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
picoxystrobin	decreases expression	1
Vorinostat	decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Cadmium	decreases expression, increases abundance	1
Clozapine	affects cotreatment, decreases expression	1
Cuprizone	affects cotreatment, decreases expression	1
Dietary Carbohydrates	decreases expression	1
Doxorubicin	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
CHEMBL5652796	Binding	Binding affinity to human VAPB 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

26 cell lines: 19 cancer cell line, 7 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_0179	BT-474	Cancer cell line	Female
CVCL_4V65	BT474-5FU[r]	Cancer cell line	Female
CVCL_4Y08	BT-474/CMV-Luc	Cancer cell line	Female
CVCL_A2GH	LR-BT474	Cancer cell line	Female
CVCL_A4AK	BT-474 Tam2	Cancer cell line	Female
CVCL_A4CL	BT-474 Ecadherin EmGFP	Cancer cell line	Female
CVCL_AQ07	BT-474 Clone 5	Cancer cell line	Female
CVCL_AR86	BT-474 Tam1	Cancer cell line	Female
CVCL_AR96	BT-474 EEI	Cancer cell line	Female
CVCL_B6RU	HeLa VAPB KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00542412	PHASE4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	PHASE4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	PHASE4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	PHASE4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	PHASE4	RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT00021697	PHASE3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	PHASE3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	PHASE3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	PHASE3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00136110	PHASE3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	PHASE3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00372879	PHASE3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
NCT00415519	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III
NCT00424463	PHASE3	COMPLETED	Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00868166	PHASE3	COMPLETED	Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
NCT00965497	PHASE3	COMPLETED	Escitalopram (Lexapro) for Depression MS or ALS
NCT01016522	PHASE3	TERMINATED	Safety and Tolerability of the Ketogenic Diet in Amyotrophic Lateral Sclerosis (ALS)
NCT01160263	PHASE3	COMPLETED	Study of Dopamine and Serotonin Transporters in Patients With Amyotrophic Lateral Sclerosis and Controls
NCT01281189	PHASE3	COMPLETED	Phase 3 Study of Dexpramipexole in ALS
NCT01492686	PHASE3	COMPLETED	Phase 3 Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis
NCT01583088	PHASE3	TERMINATED	Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation
NCT01622088	PHASE3	TERMINATED	Phase 3 Extension Study of Dexpramipexole in ALS
NCT02496767	PHASE3	COMPLETED	Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
NCT02623699	PHASE3	COMPLETED	An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
NCT02936635	PHASE3	COMPLETED	A Study for Patients Who Completed VITALITY-ALS (CY 4031)
NCT03127267	PHASE3	RECRUITING	Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients
NCT03280056	PHASE3	COMPLETED	Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients
NCT03491462	PHASE3	COMPLETED	Arimoclomol in Amyotropic Lateral Sclerosis
NCT03505021	PHASE3	COMPLETED	Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
NCT03548311	PHASE3	COMPLETED	Clinical Trial of Ultra-high Dose Methylcobalamin for ALS
NCT03690791	PHASE3	UNKNOWN	Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease
NCT03800524	PHASE3	UNKNOWN	Safety and Efficacy of TUDCA as add-on Treatment in Patients Affected by ALS
NCT03836716	PHASE3	TERMINATED	Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial
NCT03948178	PHASE3	TERMINATED	Effects of Oral Levosimendan on Respiratory Function in Patients With Amyotrophic Lateral Sclerosis (ALS): Open-Label Extension
NCT04165824	PHASE3	COMPLETED	Safety Study of Oral Edaravone Administered in Subjects With ALS
NCT04248465	PHASE3	TERMINATED	An Efficacy and Safety Study of Ravulizumab in ALS Participants
NCT04569084	PHASE3	TERMINATED	Efficacy and Safety Study of Oral Edaravone Administered in Subjects With ALS