VAV1

Summary

VAV1 (vav guanine nucleotide exchange factor 1, HGNC:12657) is a protein-coding gene on chromosome 19p13.3, encoding Proto-oncogene vav (P15498). Couples tyrosine kinase signals with the activation of the Rho/Rac GTPases, thus leading to cell differentiation and/or proliferation.

This gene is a member of the VAV gene family. The VAV proteins are guanine nucleotide exchange factors (GEFs) for Rho family GTPases that activate pathways leading to actin cytoskeletal rearrangements and transcriptional alterations. The encoded protein is important in hematopoiesis, playing a role in T-cell and B-cell development and activation. The encoded protein has been identified as the specific binding partner of Nef proteins from HIV-1. Coexpression and binding of these partners initiates profound morphological changes, cytoskeletal rearrangements and the JNK/SAPK signaling cascade, leading to increased levels of viral transcription and replication. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 7409 — RefSeq curated summary.

At a glance

• Gene–disease (curated): common variable immunodeficiency (Limited, GenCC)
• GWAS associations: 12
• Clinical variants (ClinVar): 671 total
• Phenotypes (HPO): 2
• Druggable target: yes
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• MANE Select transcript: NM_005428

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12657
Approved symbol	VAV1
Name	vav guanine nucleotide exchange factor 1
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000141968
Ensembl biotype	protein_coding
OMIM	164875
Entrez	7409

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 9 protein_coding, 5 retained_intron

ENST00000304076, ENST00000539284, ENST00000594082, ENST00000596764, ENST00000597967, ENST00000598270, ENST00000599806, ENST00000600396, ENST00000601452, ENST00000602142, ENST00000908658, ENST00000908659, ENST00000962218, ENST00000962219

RefSeq mRNA: 3 — MANE Select: NM_005428 NM_001258206, NM_001258207, NM_005428

CCDS: CCDS12174, CCDS59341, CCDS59342

Canonical transcript exons

ENST00000602142 — 27 exons

Exon	Start	End
ENSE00000667201	6852965	6853079
ENSE00000858168	6850670	6850757
ENSE00000951540	6822221	6822329
ENSE00000951541	6822419	6822514
ENSE00000951545	6826612	6826711
ENSE00000951547	6828076	6828171
ENSE00000951548	6828419	6828487
ENSE00000951595	6847998	6848114
ENSE00000951597	6853947	6854098
ENSE00001116768	6843135	6843166
ENSE00001116770	6820702	6820818
ENSE00001116771	6836432	6836568
ENSE00001116772	6821622	6821680
ENSE00001116773	6821791	6821859
ENSE00001116776	6836985	6837050
ENSE00001159272	6833908	6833953
ENSE00003092398	6857054	6857361
ENSE00003096755	6772708	6773011
ENSE00003462656	6829786	6829918
ENSE00003520280	6828815	6828900
ENSE00003529474	6825053	6825121
ENSE00003566943	6833184	6833285
ENSE00003573502	6833528	6833625
ENSE00003616809	6833711	6833733
ENSE00003627911	6825303	6825406
ENSE00003638032	6828622	6828708
ENSE00003665083	6832091	6832200

Expression profiles

Bgee: expression breadth ubiquitous, 188 present calls, max score 96.78.

FANTOM5 (CAGE): breadth broad, TPM avg 12.7641 / max 806.1018, expressed in 691 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
173512	11.9521	604
173514	0.4061	131
173511	0.3863	235
173515	0.0196	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	96.78	gold quality
monocyte	CL:0000576	95.64	gold quality
leukocyte	CL:0000738	95.45	gold quality
mononuclear cell	CL:0000842	95.39	gold quality
blood	UBERON:0000178	95.36	gold quality
spleen	UBERON:0002106	91.89	gold quality
bone marrow cell	CL:0002092	91.54	gold quality
lymph node	UBERON:0000029	90.55	gold quality
vermiform appendix	UBERON:0001154	90.11	gold quality
bone marrow	UBERON:0002371	89.16	gold quality
palpebral conjunctiva	UBERON:0001812	88.27	gold quality
bone element	UBERON:0001474	86.01	gold quality
caecum	UBERON:0001153	84.03	gold quality
epithelium of nasopharynx	UBERON:0001951	84.00	silver quality
trabecular bone tissue	UBERON:0002483	83.30	gold quality
amniotic fluid	UBERON:0000173	82.03	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	81.20	gold quality
thymus	UBERON:0002370	81.04	gold quality
upper lobe of left lung	UBERON:0008952	80.46	gold quality
tonsil	UBERON:0002372	79.86	gold quality
small intestine Peyer’s patch	UBERON:0003454	79.37	gold quality
endometrium epithelium	UBERON:0004811	78.40	gold quality
rectum	UBERON:0001052	78.37	gold quality
upper lobe of lung	UBERON:0008948	78.23	gold quality
right lung	UBERON:0002167	78.03	gold quality
mucosa of transverse colon	UBERON:0004991	77.99	gold quality
gall bladder	UBERON:0002110	77.64	gold quality
eye	UBERON:0000970	77.57	gold quality
colonic epithelium	UBERON:0000397	77.49	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.17	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.91
E-MTAB-7249	no	59.83

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): KLF2, MYB, MYC, NFKB, SPI1

miRNA regulators (miRDB)

11 targeting VAV1, 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-340-5P	100.00	72.50	4437
HSA-MIR-609	99.82	64.26	505
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-7151-5P	99.37	67.82	613
HSA-MIR-3125	99.14	68.49	2269
HSA-MIR-3916	98.99	68.04	2155
HSA-MIR-6859-5P	98.99	68.07	2049
HSA-MIR-4793-5P	96.88	65.90	872
HSA-MIR-711	96.60	65.75	528
HSA-MIR-6734-5P	95.70	65.56	950

Literature-anchored findings (GeneRIF, showing 40)

• In vitro, Vav is a regulated guanine nucleotide dissociation inhibitor for Ras (PMID:11716957)
• mechanisms by which Vav1 can regulate c-fos serum response element transcriptional activity (PMID:11859076)
• Vav exchange factor counteracts Leu3a monoclonal antibody-mediated signals inducing apoptosis and mitochondrial damage in Jurkat T cells by decreasing Bax expression. (PMID:12055221)
• Shb links SLP-76 and Vav with the CD3 complex in Jurkat T cells (SLP-76) (PMID:12084069)
• Results describe the generation of a Vav-1-deficient Jurkat T-cell line, which exhibits dramatic defects in TCR-dependent interleukin (IL)-2 promoter activation. (PMID:12234921)
• the interaction of Vav1 and Ly-GDI creates a fine tuning mechanism for the regulation of intracellular signaling pathways leading to NFAT stimulation (PMID:12386169)
• presence of a novel protein complex of CrkL, DOCK2, and Vav to regulate Rac1 in leukemia cell lines (PMID:12393632)
• A new regulatory role for Vav1 independent of its guanine exchange factor activity has been investigated in integrin-induced T cell spreading. (PMID:12496381)
• Vav1 is required for TCR-induced activation of the integrin LFA-1 and cell polarization at the immunological synapse (PMID:12616499)
• Vav is regulated by Cbl in human and mouse cells (PMID:12881521)
• Nef can modify plasma membrane GM1, affecting the behavior of HIV-infected cells towards antigen recognition and Vav towards counteracting such an effect. (PMID:12884293)
• Data show that engagement of the beta2 integrin LFA-1 on NK cells by intercellular adhesion molecule (ICAM)-1 led to phosphorylation of Vav1 that was not sensitive to cholesterol depletion or inhibition of actin polymerization. (PMID:12885870)
• Vav1 trapping was independent of actin polymerization, suggesting that inhibition of cellular cytotoxicity occurs through an early dephosphorylation of Vav1 by SHP-1, which blocks actin-dependent activation signals. (PMID:12917349)
• Vav functions as an adaptor protein responsible of targeting PI 3-K to its intranuclear substrates. (PMID:14709332)
• although both Vav proteins are biochemically coupled to the T cell antigen receptor, they regulate distinct molecular pathways leading to defined gene transcriptional events. (PMID:14757747)
• Vav1 alone is a poor activator of the JNK1 pathway in T cells (PMID:15182247)
• 3BP2 may regulate b cell receptor-mediated gene activation through Vav proteins. (PMID:15345594)
• pivotal role for Vav in the transmission of the migratory signal through the chemokine receptor CXCR4 (PMID:15618472)
• Data show that VAV1 is ectopically expressed in primary pancreatic adenocarcinomas due to demethylation of the gene promoter; identified as a growth-stimulatory protein in this disease (PMID:15652748)
• there is a phosphorylation-dependent association between beta(3) integrin and Vav1 which is essential for cell progression to a Rho-dominant phenotype during cell adhesion (PMID:15699036)
• essential role of Vav in T cells, and Vav insufficiency in common variable immunodeficiency characterized by T-cell defects (PMID:15817684)
• Isolated Vav1 cysteine-rich domain (CRD) directly associates with Rac1, and residues K116 and S83 in the proximity of the P-loop and the guanine base either are part of this binding interface or undergo a conformational change following CRD binding. (PMID:15850391)
• activation of Vav1-Rac signaling pathway by CXCL12 represents an important inside-out event controlling efficient up-regulation of alpha4beta1-dependent T lymphocyte adhesion (PMID:15872091)
• Vav plays crucial functions in the maturation process of myeloid cells. (PMID:15878332)
• CD21 activation triggered Cbl tyrosine phosphorylation, which interacts with SH2 domains of p85 subunit, SH2 domains of Crk-L and with tyrosine phosphorylated Syk kinase. CD21 activation triggers dissociation of Cbl-Vav complex. (PMID:16289966)
• Vav activity is required for fAbeta-stimulated intracellular signaling events upstream of reactive oxygen species production and phagosome formation (PMID:16728400)
• comparison of DOCK2 and Vav1 involvement in CXCL12-promoted Rac activation and alpha4beta1-dependent human T cell adhesion indicated a more prominent role of Vav1 than DOCK2 (PMID:17015707)
• Vav1 Tyr(174) is essential for maintaining the inhibitory constraint of the DH domain in both developing and mature T cells, constitutively activated Vav GEF disrupts TCR-signaling microclusters and leads to defective T cell development and proliferation (PMID:17050525)
• chemoattractant-stimulated superoxide production can be amplified by a positive feedback loop in which p67(phox) targets Vav1-mediated Rac activation (PMID:17060455)
• phosphorylation of the adaptor molecule SLP-76 is essential for recruitment of the exchange factor Vav leading to Ca(2+) flux and IL-2 production (PMID:17237383)
• Remedial strategies in structural proteomics were used for the expression, purification, and crystallization of the VAV1/RAC1 complex. (PMID:17275330)
• the calponin homology domain of Vav1 associates with calmodulin and is prerequisite to T cell antigen receptor-induced calcium release in Jurkat T lymphocytes (PMID:17550897)
• This review addresses the physiological function of wild-type Vav1, its mode of activation as an oncogene, and its emerging role as a transforming protein in human cancer. (PMID:17590270)
• The data provide the first evidence of a role of glycerophosphoinositols as modulators of T-cell signaling and establish a mechanistic basis for the effects of this phosphoinositide derivative on F-actin dynamics. (PMID:17716865)
• CD147, via the selective inhibition of specific downstream elements of the Vav1/Rac1 route, contributes to the negative regulation of T-cell responses. (PMID:18160397)
• a VAV1-Rac1-PAK1 signaling axis in mononuclear phagocytes regulating superoxide production in a stimulus-dependent manner. (PMID:18160398)
• Our findings define a pathway involving CD28 binding to Grb-2 and its co-operativity with Vav1 in the regulation of T-cell co-stimulation. (PMID:18295596)
• Structural basis of guanine nucleotide exchange mediated by the T-cell essential Vav1 is reported. (PMID:18589439)
• the Vav pathway is ramified in B-lymphocytes in additional diacylglycerol-dependent signaling branches such as those involving protein kinase C, protein kinase D, and phospholipase D (PMID:18974050)
• while Vav-1 and LAT preferentially bound to Syk, phospholipase C-gamma1 bound to both Syk and ZAP-70 (PMID:19018007)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000112526
mus_musculus	Vav1	ENSMUSG00000034116
rattus_norvegicus	Vav1	ENSRNOG00000050430

Paralogs (22): TRIO (ENSG00000038382), MCF2L2 (ENSG00000053524), PLEKHG2 (ENSG00000090924), MCF2 (ENSG00000101977), ARHGEF7 (ENSG00000102606), PLEKHG1 (ENSG00000120278), MCF2L (ENSG00000126217), ARHGEF6 (ENSG00000129675), ARHGEF9 (ENSG00000131089), VAV3 (ENSG00000134215), TIAM2 (ENSG00000146426), KIAA1755 (ENSG00000149633), PLEKHG4B (ENSG00000153404), TIAM1 (ENSG00000156299), KALRN (ENSG00000160145), VAV2 (ENSG00000160293), ARHGEF40 (ENSG00000165801), SPATA13 (ENSG00000182957), SESTD1 (ENSG00000187231), PLEKHN1 (ENSG00000187583), PLEKHG4 (ENSG00000196155), ARHGEF25 (ENSG00000240771)

Protein

Protein identifiers

Proto-oncogene vav — P15498 (reviewed: P15498)

All UniProt accessions (4): A0A0A0MR07, P15498, F5H5P4, Q96D37

UniProt curated annotations — full annotation on UniProt →

Function. Couples tyrosine kinase signals with the activation of the Rho/Rac GTPases, thus leading to cell differentiation and/or proliferation.

Subunit / interactions. Interacts with SHB. Interacts with SH2B2, GRB2, GRB3, DOCK2, SLA, TEC and ZNF655/VIK. Interacts with SIAH2; without leading to its degradation. Associates with BLNK, PLCG1, GRB2 and NCK1 in a B-cell antigen receptor-dependent fashion. Interacts with CBLB; which inhibits tyrosine phosphorylation and down-regulates activity. May interact with CCPG1. Interacts with CLNK. Interacts with THEMIS2. Interacts with NEK3 and this interaction is prolactin-dependent. Interacts with ITK. Interacts with PTK2B/PYK2. Interacts with HCK. Interacts with PTK2B/PYK2. Interacts (via SH2 domain) with SYK. Interacts with ANKRD54. Interacts with CD6. Interacts with isoform 2 of CRACR2A. Interacts with LCP2; this interaction plays a role in TCR-mediated cytokine production.

Tissue specificity. Widely expressed in hematopoietic cells but not in other cell types.

Post-translational modifications. Phosphorylated on tyrosine residues by HCK in response to IFNG and bacterial lipopolysaccharide (LPS). Phosphorylated by FYN.

Domain organisation. The DH domain is involved in interaction with CCPG1.

Miscellaneous. ‘Vav’ stands for the sixth letter of the Hebrew alphabet.

Isoforms (2)

UniProt ID	Names	Canonical?
P15498-1	1	yes
P15498-2	2

RefSeq proteins (3): NP_001245135, NP_001245136, NP_005419* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000219	DH_dom	Domain
IPR000980	SH2	Domain
IPR001331	GDS_CDC24_CS	Conserved_site
IPR001452	SH3_domain	Domain
IPR001715	CH_dom	Domain
IPR001849	PH_domain	Domain
IPR002219	PKC_DAG/PE	Domain
IPR003096	SM22_calponin	Family
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR022613	CH_CAMSAP_2	Domain
IPR035729	VAV1_SH3_2	Domain
IPR035730	VAV1_SH3_1	Domain
IPR035879	VAV1_SH2	Domain
IPR035899	DBL_dom_sf	Homologous_superfamily
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR036872	CH_dom_sf	Homologous_superfamily
IPR037832	PH_Vav	Domain

Pfam: PF00017, PF00018, PF00130, PF00169, PF00621, PF11971

UniProt features (81 total): helix 35, strand 21, turn 8, domain 6, sequence conflict 3, mutagenesis site 2, modified residue 2, chain 1, splice variant 1, sequence variant 1, zinc finger region 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
6NEW	X-RAY DIFFRACTION	2.5
3BJI	X-RAY DIFFRACTION	2.6
6NF1	X-RAY DIFFRACTION	2.6
6NFA	X-RAY DIFFRACTION	2.7
3KY9	X-RAY DIFFRACTION	2.73
9NFR	X-RAY DIFFRACTION	3.4
2CRH	SOLUTION NMR
2LCT	SOLUTION NMR
2MC1	SOLUTION NMR
2ROR	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P15498-F1	86.63	0.62

Functional residue map

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

Post-translational modifications (2): 826, 844

Mutagenesis-validated functional residues (2):

Position	Phenotype
529	abolishes transforming activity.
696	loss of interaction with syk.

Function

Pathways and Gene Ontology

Reactome pathways

24 pathways

ID	Pathway
R-HSA-114604	GPVI-mediated activation cascade
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-1433557	Signaling by SCF-KIT
R-HSA-193648	NRAGE signals death through JNK
R-HSA-2029482	Regulation of actin dynamics for phagocytic cup formation
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-2871796	FCERI mediated MAPK activation
R-HSA-2871809	FCERI mediated Ca+2 mobilization
R-HSA-389359	CD28 dependent Vav1 pathway
R-HSA-416482	G alpha (12/13) signalling events
R-HSA-4420097	VEGFA-VEGFR2 Pathway
R-HSA-512988	Interleukin-3, Interleukin-5 and GM-CSF signaling
R-HSA-5218920	VEGFR2 mediated vascular permeability
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9013404	RAC2 GTPase cycle
R-HSA-9013408	RHOG GTPase cycle
R-HSA-9027284	Erythropoietin activates RAS
R-HSA-912631	Regulation of signaling by CBL
R-HSA-9664422	FCGR3A-mediated phagocytosis
R-HSA-9679191	Potential therapeutics for SARS
R-HSA-9748787	Azathioprine ADME
R-HSA-983695	Antigen activates B Cell Receptor (BCR) leading to generation of second messengers

MSigDB gene sets: 375 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, GOBP_REGULATION_OF_CELL_ACTIVATION, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_B_CELL_ACTIVATION, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, GOBP_PLATELET_ACTIVATION, MODULE_45, GOBP_LYMPHOCYTE_COSTIMULATION, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_VASCULAR_ENDOTHELIAL_GROWTH_FACTOR_RECEPTOR_SIGNALING_PATHWAY, GOBP_B_CELL_PROLIFERATION

GO Biological Process (27): immune response-regulating cell surface receptor signaling pathway (GO:0002768), G protein-coupled receptor signaling pathway (GO:0007186), integrin-mediated signaling pathway (GO:0007229), small GTPase-mediated signal transduction (GO:0007264), regulation of cell size (GO:0008361), cell migration (GO:0016477), natural killer cell activation (GO:0030101), platelet activation (GO:0030168), T cell differentiation (GO:0030217), neutrophil chemotaxis (GO:0030593), T cell costimulation (GO:0031295), Fc-epsilon receptor signaling pathway (GO:0038095), Fc-gamma receptor signaling pathway involved in phagocytosis (GO:0038096), B cell proliferation (GO:0042100), natural killer cell mediated cytotoxicity (GO:0042267), positive regulation of natural killer cell mediated cytotoxicity (GO:0045954), vascular endothelial growth factor receptor signaling pathway (GO:0048010), regulation of small GTPase mediated signal transduction (GO:0051056), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), cellular response to xenobiotic stimulus (GO:0071466), reactive oxygen species metabolic process (GO:0072593), phagocytosis (GO:0006909), immune response (GO:0006955), response to xenobiotic stimulus (GO:0009410), intracellular signal transduction (GO:0035556), T cell activation (GO:0042110), positive regulation of cell adhesion (GO:0045785)

GO Molecular Function (6): phosphotyrosine residue binding (GO:0001784), guanyl-nucleotide exchange factor activity (GO:0005085), zinc ion binding (GO:0008270), phosphorylation-dependent protein binding (GO:0140031), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (4): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), cell-cell junction (GO:0005911)

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
RHO GTPase cycle	4
Fc epsilon receptor (FCERI) signaling	2
Platelet activation, signaling and aggregation	1
Intracellular signaling by second messengers	1
Signaling by Receptor Tyrosine Kinases	1
Cell death signalling via NRAGE, NRIF and NADE	1
Fcgamma receptor (FCGR) dependent phagocytosis	1
PI3K/AKT Signaling in Cancer	1
Co-stimulation by CD28	1
GPCR downstream signalling	1
Signaling by VEGF	1
Signaling by Interleukins	1
VEGFA-VEGFR2 Pathway	1
Negative regulation of the PI3K/AKT network	1
Signaling by Erythropoietin	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell surface receptor signaling pathway	2
cellular anatomical structure	2
immune response-regulating signaling pathway	1
G protein-coupled receptor activity	1
signal transduction	1
intracellular signaling cassette	1
regulation of cellular component size	1
cell motility	1
lymphocyte activation	1
cell activation	1
blood coagulation	1
lymphocyte differentiation	1
T cell activation	1
granulocyte chemotaxis	1
neutrophil migration	1
lymphocyte costimulation	1
positive regulation of T cell activation	1
Fc receptor signaling pathway	1
Fc receptor mediated stimulatory signaling pathway	1
phagocytosis	1
Fc-gamma receptor signaling pathway	1
B cell activation	1
lymphocyte proliferation	1
leukocyte mediated cytotoxicity	1
natural killer cell mediated immunity	1
positive regulation of leukocyte mediated cytotoxicity	1
positive regulation of natural killer cell mediated immunity	1
natural killer cell mediated cytotoxicity	1
regulation of natural killer cell mediated cytotoxicity	1
cell surface receptor protein tyrosine kinase signaling pathway	1
small GTPase-mediated signal transduction	1
regulation of intracellular signal transduction	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
positive regulation of intracellular signal transduction	1
response to xenobiotic stimulus	1
cellular response to chemical stimulus	1
protein phosphorylated amino acid binding	1
GTP binding	1
GDP binding	1

Protein interactions and networks

STRING

2662 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VAV1	LCP2	Q13094	998
VAV1	SYK	P43405	998
VAV1	ZAP70	P43403	993
VAV1	BLNK	Q8WV28	991
VAV1	NCK1	P16333	988
VAV1	BTK	Q06187	988
VAV1	LYN	P07948	987
VAV1	GRB2	P29354	985
VAV1	GRAP2	O75791	984
VAV1	PLCG2	P16885	982
VAV1	ITK	Q08881	978
VAV1	CDC42	P21181	978
VAV1	LCK	P06239	967
VAV1	PLCG1	P19174	964
VAV1	SOS1	Q07889	963

IntAct

81 interactions, top by confidence:

A	B	Type	Score
VAV1	SH3BP2	psi-mi:“MI:0915”(physical association)	0.790
SH3BP2	VAV1	psi-mi:“MI:0915”(physical association)	0.790
SH3BP2	VAV1	psi-mi:“MI:0914”(association)	0.790
VAV1	SH3BP2	psi-mi:“MI:0914”(association)	0.790
PTPN22	LCK	psi-mi:“MI:0914”(association)	0.780
VAV1	LCP2	psi-mi:“MI:0914”(association)	0.760
VAV1	GRB2	psi-mi:“MI:0915”(physical association)	0.660
GRB2	VAV1	psi-mi:“MI:2364”(proximity)	0.660
VAV1	ABL1	psi-mi:“MI:0915”(physical association)	0.600
ABL1	VAV1	psi-mi:“MI:0915”(physical association)	0.600
ABL1	VAV1	psi-mi:“MI:0407”(direct interaction)	0.600
VAV1	ZNF655	psi-mi:“MI:0915”(physical association)	0.580
ZNF655	VAV1	psi-mi:“MI:0915”(physical association)	0.580

BioGRID (299): VAV1 (Two-hybrid), EZH2 (Two-hybrid), MS4A2 (Affinity Capture-Western), VAV1 (PCA), KLK7 (Affinity Capture-MS), PLBD1 (Affinity Capture-MS), NUB1 (Affinity Capture-MS), SPECC1L (Affinity Capture-MS), SERPINA12 (Affinity Capture-MS), PALM2-AKAP2 (Affinity Capture-MS), APLP2 (Affinity Capture-MS), ACTBL2 (Affinity Capture-MS), SDR9C7 (Affinity Capture-MS), SERPINB2 (Affinity Capture-MS), APBB2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2JTR4, A1A4S6, A4II46, A6H6A9, A6NI28, A6QNS3, A7MBL8, A8KBF6, B5DFQ4, O60890, O94806, P0CAX5, P15498, P23727, P26450, P27870, P27986, P54100, Q02384, Q07889, Q07890, Q08DN7, Q08DP6, Q12979, Q15139, Q16513, Q5R685, Q5SSL4, Q5U4T3, Q5ZJ17, Q5ZLX4, Q5ZMW5, Q62101, Q62245, Q63787, Q6NRC7, Q6PCS4, Q6Y5D8, Q6ZM89, Q6ZQ82

Diamond homologs: A1IGU3, A1IGU4, A1IGU5, A1ZAY1, E7F1U2, O15068, O15085, O77775, P10569, P15498, P19878, P35991, Q08DN7, Q3LAC4, Q5DU57, Q60992, Q63406, Q69ZK0, Q70Z35, Q80VK6, Q8TCU6, Q96N96, Q9NHV9, Q9NXL2, O60229, P40995, Q1LUA6, Q5BKC9, Q5RDX5, Q64096, Q6RFZ7, Q8CHT1, Q8N5V2, Q9ES67, A0JNB0, A1A5H8, A1Y2K1, A6QLK6, F1LM93, F1RDG9

SIGNOR signaling

26 interactions.

A	Effect	B	Mechanism
SYK	up-regulates	VAV1	phosphorylation
VAV1	up-regulates	SYK	binding
ABL1	up-regulates	VAV1	phosphorylation
BCR-ABL	up-regulates	VAV1	phosphorylation
VAV1	up-regulates	ERK1/2
LAT	“up-regulates activity”	VAV1	binding
DNM2	“up-regulates quantity by stabilization”	VAV1	binding
VAV1	“up-regulates activity”	RHOA	“guanine nucleotide exchange factor”
VAV1	“up-regulates activity”	RAC1	“guanine nucleotide exchange factor”
VAV1	“up-regulates activity”	ZAP70	binding
PTPN6	“down-regulates activity”	VAV1	dephosphorylation
ZAP70	“up-regulates activity”	VAV1	phosphorylation
SRC	“up-regulates activity”	VAV1	phosphorylation
VAV1	up-regulates	GRAP	binding
VAV1	up-regulates	MAPK1
VAV1	up-regulates	CBL	binding
VAV1	up-regulates	GRB2	binding
VAV1	up-regulates	PRKCQ
FYN	up-regulates	VAV1	phosphorylation
CD19	“up-regulates activity”	VAV1	binding
LCK	unknown	VAV1	phosphorylation
SOCS1	“down-regulates quantity by destabilization”	VAV1	binding
VCB-Cul2	“down-regulates quantity by destabilization”	VAV1	polyubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 42 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
Constitutive Signaling by EGFRvIII	6	133.8×	3e-10
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	6	107.1×	1e-09
Signaling by ERBB2 ECD mutants	5	105.0×	3e-08
DAP12 signaling	9	103.6×	3e-14
GAB1 signalosome	5	99.1×	3e-08
Regulation of signaling by CBL	6	93.1×	2e-09
GPVI-mediated activation cascade	9	86.8×	8e-14
Signaling by ERBB2 KD Mutants	5	66.1×	3e-07

GO biological processes:

GO term	Partners	Fold	FDR
epidermal growth factor receptor signaling pathway	6	43.7×	2e-06
T cell receptor signaling pathway	9	40.2×	7e-10
integrin-mediated signaling pathway	5	23.6×	2e-04
regulation of actin cytoskeleton organization	5	23.2×	2e-04
neuron migration	5	19.7×	3e-04
actin cytoskeleton organization	7	16.3×	3e-05
positive regulation of MAPK cascade	6	14.2×	2e-04
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	6	13.8×	2e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — LUAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	274
Likely benign	325
Benign	25

Top pathogenic / likely-pathogenic (0)

SpliceAI

3587 predictions. Top by Δscore:

Variant	Effect	Δscore
19:6820699:C:G	acceptor_gain	1.0000
19:6820699:CA:C	acceptor_loss	1.0000
19:6820700:A:AG	acceptor_gain	1.0000
19:6820700:AG:A	acceptor_loss	1.0000
19:6820701:G:GA	acceptor_gain	1.0000
19:6820701:GT:G	acceptor_gain	1.0000
19:6820701:GTT:G	acceptor_gain	1.0000
19:6820701:GTTC:G	acceptor_gain	1.0000
19:6820701:GTTCC:G	acceptor_gain	1.0000
19:6820814:GCAAG:G	donor_gain	1.0000
19:6820819:G:GG	donor_gain	1.0000
19:6821681:G:GG	donor_gain	1.0000
19:6821860:G:GG	donor_gain	1.0000
19:6822219:A:AG	acceptor_gain	1.0000
19:6822220:G:GG	acceptor_gain	1.0000
19:6822220:GC:G	acceptor_gain	1.0000
19:6822220:GCGAC:G	acceptor_gain	1.0000
19:6822326:GCCG:G	donor_gain	1.0000
19:6822328:CGG:C	donor_loss	1.0000
19:6822330:G:GA	donor_loss	1.0000
19:6822330:G:GG	donor_gain	1.0000
19:6822410:C:CA	acceptor_gain	1.0000
19:6822415:TCAGC:T	acceptor_loss	1.0000
19:6822416:CA:C	acceptor_loss	1.0000
19:6822417:A:AG	acceptor_gain	1.0000
19:6822418:G:GA	acceptor_gain	1.0000
19:6822418:GCCCA:G	acceptor_gain	1.0000
19:6822481:G:GT	donor_gain	1.0000
19:6822510:AGCAG:A	donor_loss	1.0000
19:6822511:GCAG:G	donor_gain	1.0000

AlphaMissense

5597 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:6772817:T:A	W4R	1.000
19:6772817:T:C	W4R	1.000
19:6772835:T:A	W10R	1.000
19:6772835:T:C	W10R	1.000
19:6772839:T:C	L11P	1.000
19:6772908:C:A	A34D	1.000
19:6772917:T:A	L37H	1.000
19:6772917:T:C	L37P	1.000
19:6772920:G:C	R38P	1.000
19:6772923:A:T	D39V	1.000
19:6772925:G:C	G40R	1.000
19:6772926:G:A	G40D	1.000
19:6772926:G:T	G40V	1.000
19:6772944:T:C	L46P	1.000
19:6820793:T:A	L99H	1.000
19:6820793:T:C	L99P	1.000
19:6822301:T:C	L177P	1.000
19:6822485:T:C	Y209H	1.000
19:6825056:T:C	F220L	1.000
19:6825058:C:A	F220L	1.000
19:6825058:C:G	F220L	1.000
19:6828106:T:C	F320L	1.000
19:6828107:T:C	F320S	1.000
19:6828108:C:A	F320L	1.000
19:6828108:C:G	F320L	1.000
19:6828122:T:C	L325P	1.000
19:6828125:T:C	L326P	1.000
19:6828134:C:A	P329H	1.000
19:6828134:C:G	P329R	1.000
19:6828141:G:C	Q331H	1.000

dbSNP variants (sampled 300 via entrez): RS1000014023 (19:6787752 C>A,T), RS1000018546 (19:6828594 G>A,T), RS1000073750 (19:6793043 C>T), RS1000077637 (19:6829086 G>C,T), RS1000105619 (19:6855362 G>A), RS1000118671 (19:6823287 G>A), RS1000201269 (19:6807584 G>A), RS1000206526 (19:6838791 G>A), RS1000214423 (19:6776919 G>A,C), RS1000234834 (19:6844360 C>A), RS1000246728 (19:6855559 C>A), RS1000261082 (19:6855308 C>G,T), RS1000262396 (19:6807847 T>G), RS1000315314 (19:6812586 G>A), RS1000335713 (19:6776987 C>A)

Disease associations

OMIM: gene MIM:164875 | disease phenotypes: MIM:209850, MIM:607834

GenCC curated gene-disease

Disease	Classification	Inheritance
common variable immunodeficiency	Limited	Autosomal dominant

Mondo (7): precocious puberty (MONDO:0000088), autism (MONDO:0005260), flatfoot (MONDO:0005293), hearing loss disorder (MONDO:0005365), attention deficit-hyperactivity disorder (MONDO:0007743), anxiety (MONDO:0011918), common variable immunodeficiency (MONDO:0015517)

Orphanet (1): Rare precocious puberty (Orphanet:95708)

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0000826	Precocious puberty
HP:0000717	Autism

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST001888_3	Periodontitis	8.000000e-07
GCST004599_141	Mean platelet volume	4.000000e-10
GCST004599_142	Mean platelet volume	2.000000e-12
GCST004616_38	Platelet distribution width	4.000000e-19
GCST004616_39	Platelet distribution width	5.000000e-09
GCST006585_259	Blood protein levels	6.000000e-14
GCST90002388_34	Lymphocyte count	4.000000e-09
GCST90002395_398	Mean platelet volume	6.000000e-36
GCST90002395_399	Mean platelet volume	5.000000e-17
GCST90002401_246	Platelet distribution width	7.000000e-40
GCST90002401_247	Platelet distribution width	1.000000e-13
GCST90002402_612	Platelet count	7.000000e-18

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007984	platelet component distribution width
EFO:0004587	lymphocyte count
EFO:0004309	platelet count

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D001007	Anxiety	F01.470.132
D001321	Autistic Disorder	F03.625.164.113.500
D017074	Common Variable Immunodeficiency	C20.673.330
D005413	Flatfoot	C05.330.488.655.250; C05.330.495.681.250; C05.660.585.512.380.813.250; C16.131.621.585.512.500.681.250
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D011629	Puberty, Precocious	C19.391.693

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3259472 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — Rho GEFs

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
8.98	Kd	1.05	nM	CHEMBL27768

PubChem BioAssay actives

1 with measured affinity, of 1 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
[(1S,2S,6R,10S,11R,13S,14R,15R)-13-butanoyloxy-1,6-dihydroxy-8-(hydroxymethyl)-4,12,12,15-tetramethyl-5-oxo-14-tetracyclo[8.5.0.02,6.011,13]pentadeca-3,8-dienyl] butanoate	1138941: Binding affinity to VAV1 C1 domain (unknown origin)	kd	0.0010	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic	increases methylation, affects cotreatment, increases abundance, increases expression	2
Nickel	decreases expression, increases expression	2
Tretinoin	affects cotreatment, increases expression	2
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
sodium arsenite	affects cotreatment, increases abundance, increases expression	1
butyraldehyde	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
pentanal	increases expression	1
tamibarotene	increases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
licochalcone B	increases expression	1
jinfukang	decreases expression, increases reaction	1
gardiquimod	increases expression, decreases reaction	1
Resveratrol	increases reaction, increases phosphorylation, affects binding, decreases reaction	1
Arsenic Trioxide	affects cotreatment, increases expression	1
Air Pollutants, Occupational	decreases expression	1
Aldehydes	increases expression	1
Aspirin	decreases expression	1
Atrazine	increases expression	1
Azathioprine	increases expression	1
Benzo(a)pyrene	increases methylation	1
Cisplatin	decreases expression, increases reaction	1
Diuron	decreases expression	1
Environmental Pollutants	affects expression	1
Inositol Phosphates	increases activity, increases chemical synthesis, affects binding	1
Manganese	affects cotreatment, increases abundance, increases expression	1
N-Formylmethionine Leucyl-Phenylalanine	increases phosphorylation	1
Silicon Dioxide	increases 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
CHEMBL3268112	Binding	Binding affinity to VAV1 C1 domain (unknown origin)	Diacylglycerol lactones targeting the structural features that distinguish the atypical C1 domains of protein kinase C ζ and ι from typical C1 domains. — J 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_B2KV	Abcam HeLa VAV1 KO	Cancer cell line	Female
CVCL_B8AD	Abcam Raji VAV1 KO	Cancer cell line	Male
CVCL_C0B8	Abcam THP-1 VAV1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00520494	PHASE4	COMPLETED	Efficacy and Safety of Vivaglobin® in Previously Untreated Patients With Primary Immunodeficiency
NCT01289847	PHASE4	COMPLETED	A Study to Find Out How Safe and Effective Gammaplex® is in Young People With Primary Immunodeficiency
NCT01946906	PHASE4	COMPLETED	The Rifaximin Study in CVID
NCT05193552	PHASE4	RECRUITING	Usage of Spirometry in Managing IgG Therapy in CVID With Airway Disease
NCT03963752	PHASE4	COMPLETED	Clinical Trial of Rapid Progressive Central Precocious Puberty With Integrative Chinese and Western Medicine
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT00168012	PHASE3	COMPLETED	Efficacy and Safety of Intravenous Immunoglobulin IVIG-F10 in Patients With Primary Immunodeficiencies (PID)
NCT00168025	PHASE3	COMPLETED	Efficacy and Safety of Intravenous Immunoglobulin IgPro10 in Patients With Primary Immunodeficiencies (PID)
NCT00220766	PHASE3	COMPLETED	Rapid Infusion of Immune Globulin Intravenous (Human) In Primary Immunodeficiency Patients
NCT00322556	PHASE3	COMPLETED	Safety and Efficacy of Intravenous Immunoglobulin IgPro10 in Patients With Primary Immunodeficiencies (PID)
NCT00542997	PHASE3	COMPLETED	Study of Subcutaneous Immune Globulin in Patients Requiring IgG Replacement Therapy
NCT01884311	PHASE3	COMPLETED	Pharmacokinetics (PK) and Safety of Subgam-VF in Primary Immunodeficiency Diseases