VAV2

Summary

VAV2 (vav guanine nucleotide exchange factor 2, HGNC:12658) is a protein-coding gene on chromosome 9q34.2, encoding Guanine nucleotide exchange factor VAV2 (P52735). Guanine nucleotide exchange factor for the Rho family of Ras-related GTPases.

VAV2 is the second member of the VAV guanine nucleotide exchange factor family of oncogenes. Unlike VAV1, which is expressed exclusively in hematopoietic cells, VAV2 transcripts were found in most tissues. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 7410 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 195 total
• MANE Select transcript: NM_001134398

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12658
Approved symbol	VAV2
Name	vav guanine nucleotide exchange factor 2
Location	9q34.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000160293
Ensembl biotype	protein_coding
OMIM	600428
Entrez	7410

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 16 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000371850, ENST00000371851, ENST00000406606, ENST00000472905, ENST00000486113, ENST00000876885, ENST00000876886, ENST00000876887, ENST00000923292, ENST00000923293, ENST00000954042, ENST00000954043, ENST00000954044, ENST00000954045, ENST00000954046, ENST00000954047, ENST00000954048, ENST00000954049

RefSeq mRNA: 3 — MANE Select: NM_001134398 NM_001134398, NM_001411028, NM_003371

CCDS: CCDS48053, CCDS6979, CCDS94524

Canonical transcript exons

ENST00000371850 — 30 exons

Exon	Start	End
ENSE00001051196	133797710	133797809
ENSE00001051198	133796429	133796524
ENSE00001051199	133795668	133795736
ENSE00001051205	133812114	133812216
ENSE00001051207	133809040	133809138
ENSE00001051214	133807258	133807326
ENSE00001051220	133806081	133806181
ENSE00001096231	133769417	133769503
ENSE00001096237	133771959	133772046
ENSE00001096243	133768442	133768596
ENSE00001096246	133784317	133784418
ENSE00001096247	133785776	133785885
ENSE00001096253	133789258	133789343
ENSE00001096259	133788354	133788486
ENSE00001096262	133778762	133778889
ENSE00001096267	133834272	133834340
ENSE00001096269	133776028	133776080
ENSE00001096272	133770378	133770501
ENSE00001096274	133774935	133775051
ENSE00001133974	133777389	133777463
ENSE00001133992	133783503	133783591
ENSE00001134002	133791783	133791869
ENSE00001134180	133861374	133861432
ENSE00001388876	133779918	133779939
ENSE00001456304	133761894	133764109
ENSE00001894042	133992075	133992324
ENSE00002407897	133780694	133780710
ENSE00002418466	133787246	133787260
ENSE00002421895	133810191	133810205
ENSE00003514912	133939103	133939219

Expression profiles

Bgee: expression breadth ubiquitous, 248 present calls, max score 93.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.2664 / max 198.7476, expressed in 1731 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
103040	9.0756	1569
103042	8.5344	1675
103041	1.7069	1096
103043	0.7144	471
103039	0.2351	111

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	93.81	gold quality
ganglionic eminence	UBERON:0004023	91.73	gold quality
ventricular zone	UBERON:0003053	91.41	gold quality
cortical plate	UBERON:0005343	91.29	gold quality
body of pancreas	UBERON:0001150	91.27	gold quality
right lobe of liver	UBERON:0001114	91.07	gold quality
caput epididymis	UBERON:0004358	89.99	gold quality
right adrenal gland cortex	UBERON:0035827	89.60	gold quality
corpus epididymis	UBERON:0004359	89.05	gold quality
adrenal cortex	UBERON:0001235	88.90	gold quality
right adrenal gland	UBERON:0001233	88.83	gold quality
left adrenal gland cortex	UBERON:0035825	88.79	gold quality
jejunal mucosa	UBERON:0000399	88.64	gold quality
left adrenal gland	UBERON:0001234	88.53	gold quality
liver	UBERON:0002107	88.31	gold quality
sural nerve	UBERON:0015488	88.24	gold quality
pancreas	UBERON:0001264	87.89	gold quality
adrenal gland	UBERON:0002369	87.70	gold quality
duodenum	UBERON:0002114	87.67	gold quality
metanephros cortex	UBERON:0010533	86.29	gold quality
renal medulla	UBERON:0000362	86.12	gold quality
tibia	UBERON:0000979	85.79	gold quality
small intestine Peyer’s patch	UBERON:0003454	85.69	gold quality
small intestine	UBERON:0002108	85.41	gold quality
germinal epithelium of ovary	UBERON:0001304	85.37	gold quality
lower lobe of lung	UBERON:0008949	85.32	gold quality
colonic mucosa	UBERON:0000317	85.19	gold quality
cartilage tissue	UBERON:0002418	84.55	gold quality
visceral pleura	UBERON:0002401	84.46	gold quality
adult mammalian kidney	UBERON:0000082	84.35	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-119	yes	24.61
E-ANND-3	yes	4.24

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA1

miRNA regulators (miRDB)

137 targeting VAV2, 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-513A-5P	100.00	69.77	2465
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-371B-5P	99.99	75.34	4759
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-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-185-3P	99.95	67.01	1743
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-3912-5P	99.95	66.11	925

Literature-anchored findings (GeneRIF, showing 40)

• Vav2 is a GDP/GTP exchange factor (GEF) for Rac in vivo. (PMID:11448999)
• Critical but distinct roles for the pleckstrin homology and cysteine-rich domains as positive modulators of Vav2 signaling and transformation. (PMID:11909943)
• Vav2 and Tiam1 may act as downstream effectors of Src, thereby regulating Rac1-dependent pathways that participate in Src-induced cell transformation (PMID:12810717)
• 3BP2 may regulate b cell receptor-mediated gene activation through Vav proteins. (PMID:15345594)
• Rap1 promotes cell spreading by localizing a subset of Rac GEFs to sites of active lamellipodia extension (PMID:15479739)
• Vav2-mediated nucleotide exchange of Rho GTPases follows the Theorell-Chance catalytic mechanism in which Vav2.Rho GTPase complex is the major species during the exchange process and Vav2.GDP-Mg2+.Rho GTPase ternary complex is present only transiently. (PMID:15850391)
• The EGFR/Vav2/Rac1 axis is a crucial pathway for the acquisition of motile and invasive properties of most head and neck squamous cell carcinoma cells. (PMID:17234718)
• Vav2 acts downstream of VEGF to activate Rac1. (PMID:17686471)
• IMC-C225 cross-links integrins with EGFR, leading to Vav2-dependent activation of RhoA (PMID:18829495)
• Interaction of L2 with Vav2 was mediated by the N-terminus of L2 and independent of the N-terminus of Vav2. (PMID:19451809)
• RhoA knockdown intensified the Vav2-induced disruption of acini, leading to more aggressive cell outgrowth and branching morphogenesis. (PMID:19826000)
• Vav2 can regulate growth factors receptor signalling by slowing receptor internalization and degradation through its interaction with endosome-associated proteins. (PMID:20140013)
• Data strongly suggest that VAV2 and VAV3 genes are susceptibility loci in Japanese primary open-angle glaucoma. (PMID:20140222)
• Together, we suggest that balanced Vav2 activity is necessary for optimal neurite outgrowth and promotes branching by targeting GEF activity to branch points. (PMID:20298788)
• present data indicate a lack of involvement of variations in NTF4, VAV2, and VAV3 with glaucoma pathogenesis in an Indian population. (PMID:20463313)
• VAV2 has been identified as a candidate gene in a genome-wide association study of German multiple sclerosis patients. (PMID:20598377)
• Type IV pili producing Neisseria gonorrhoeae triggers a phosphotyrosine-dependent Cav1-Vav2-RhoA signaling cascade that elicits cytoskeletal rearrangements and effectively impedes bacterial uptake into host cells. (PMID:20808760)
• VAV2 specifically interacts with activated Galpha(q) but not with Galpha(s) subunits, competing with parathyroid hormone receptor for coupling to Galpha(q). (PMID:22554804)
• The structural basis for the interaction between Arap3 and Vav2, hydrophobic pockets and binding specificity. (PMID:22750419)
• Upregulation of Rac1 activity by Wnt3a temporally correlated with enhanced p120-catenin binding to Rac1 and Vav2. (PMID:22946057)
• Studies indicate relevance of P-Rex1 and P-Rex2a, in breast tumorigenesis, and suggest that the exchange factors Vav2 and Vav3 play synergistic roles in breast cancer by sustaining tumor growth, neoangiogenesis, and metastasis. (PMID:23033535)
• Data indicate that Vav2 and Vav3 controlled a vast transcriptional program in breast cancer cells through mechanisms that were shared between the two proteins, isoform-specific or synergistic. (PMID:23033540)
• Two variants of VAV2 and VAV3, rs2156323 and rs2801219, respectively, were identified in Japanese patients with primary open angle glaucoma, normal tension glaucoma, and developmental glaucoma. (PMID:23402756)
• Data suggest a coordination between paxillin kinase linker (PKL)/Vav2 signaling and PKL/beta-PIX signaling during cell migration. (PMID:23615439)
• the guanine nucleotide exchange factor (GEF) Vav2 is identified as a candidate partner for KCC3. (PMID:23724134)
• VAV2 is required for Met signaling in the perinuclear endosome. (PMID:24835487)
• Authors propose a model whereby vimentin promotes FAK stabilization through VAV2-mediated Rac1 activation. This model may explain why vimentin expressing metastatic lung cancer cells are more motile and invasive. (PMID:24858039)
• Our data provide the first evidence to implicate VAV2 in glucose-induced Rac1 activation, actin remodelling and glucose-stimulated insulin secretion in pancreatic beta cells. (PMID:26224100)
• High VAV2 expression is associated with breast cancer. (PMID:26910843)
• The crystal structure of the complex between a phosphorylated PPxY motif of TXNIP and the SH2 domain of Vav2 reveals a conserved recognition mechanism. (PMID:26919541)
• work suggested that EphB3 acted as a tumor promoter in Papillary Thyroid Cancer by increasing the in vitro migration as well as the in vivo metastasis of Papillary Thyroid Cancer cells through regulating the activities of Vav2 and Rho GTPases in a kinase-dependent manner. (PMID:27986811)
• VAV2 polymorphisms associate with cardiovascular risk factors and target organ damage. (PMID:28157227)
• Manipulating steroidogenic factor-1 (SF-1) and nucleotide exchange factor VAV-2 (VAV2) abundance in cultured adrenocortical carcinoma (ACC) cells indicate that VAV2 was a critical factor for SF-1-induced cytoskeletal remodeling and invasion in culture and in vivo (chicken chorioallantoic membrane) models. (PMID:28270555)
• autocrine VEGF and IL-8 promoted endothelial cell migration via the Src/Vav2/Rac1/PAK1 signaling pathway. (PMID:28278510)
• Data indicate that phosphorylated cortactin recruits Vav2 to activate Rac3 and promote invadopodial maturation in invasive breast cancer cells. (PMID:28356423)
• We concluded that Vav2 might promote invasion and metastasis of gastric cancer by regulating some invasion and metastasis-related genes. (PMID:28459214)
• Study found that Vav2, is overexpressed in human prostate cancer and enhanced AR and AR splicing variant activity. (PMID:28811363)
• Both erb-b2 receptor tyrosine kinase 2 (ErbB2) and vav guanine nucleotide exchange factor 2 (VAV2 )are direct targets of miR-331-3p. (PMID:30955235)
• SNHG3 silencing suppresses the malignant development of triple-negative breast cancer cells by regulating miRNA-326/integrin alpha5 axis and inactivating Vav2/Rac1 signaling pathway. (PMID:32495883)
• Biochemical and NMR characterization of the interactions of Vav2-SH2 domain with lipids and the EphA2 juxtamembrane region on membrane. (PMID:32897354)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	vav2	ENSDARG00000044718
mus_musculus	Vav2	ENSMUSG00000009621
rattus_norvegicus	Vav2	ENSRNOG00000007422

Paralogs (22): TRIO (ENSG00000038382), MCF2L2 (ENSG00000053524), PLEKHG2 (ENSG00000090924), MCF2 (ENSG00000101977), ARHGEF7 (ENSG00000102606), PLEKHG1 (ENSG00000120278), MCF2L (ENSG00000126217), ARHGEF6 (ENSG00000129675), ARHGEF9 (ENSG00000131089), VAV3 (ENSG00000134215), VAV1 (ENSG00000141968), TIAM2 (ENSG00000146426), KIAA1755 (ENSG00000149633), PLEKHG4B (ENSG00000153404), TIAM1 (ENSG00000156299), KALRN (ENSG00000160145), ARHGEF40 (ENSG00000165801), SPATA13 (ENSG00000182957), SESTD1 (ENSG00000187231), PLEKHN1 (ENSG00000187583), PLEKHG4 (ENSG00000196155), ARHGEF25 (ENSG00000240771)

Protein

Protein identifiers

Guanine nucleotide exchange factor VAV2 — P52735 (reviewed: P52735)

All UniProt accessions (1): P52735

UniProt curated annotations — full annotation on UniProt →

Function. Guanine nucleotide exchange factor for the Rho family of Ras-related GTPases. Plays an important role in angiogenesis. Its recruitment by phosphorylated EPHA2 is critical for EFNA1-induced RAC1 GTPase activation and vascular endothelial cell migration and assembly.

Subunit / interactions. Interacts (via SH2 domains) with the phosphorylated form of EPHA2. Interacts with SSX2IP. Interacts with NEK3 and PRLR and this interaction is prolactin-dependent.

Tissue specificity. Widely expressed.

Post-translational modifications. Phosphorylated on tyrosine residues in response to FGR activation.

Isoforms (3)

UniProt ID	Names	Canonical?
P52735-1	1	yes
P52735-2	2
P52735-3	3

RefSeq proteins (3): NP_001127870, NP_001397957, NP_003362 (=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
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR022613	CH_CAMSAP_2	Domain
IPR035732	VAV2_SH3_2	Domain
IPR035733	VAV2_SH3_1	Domain
IPR035880	VAV2_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
IPR055251	SOS1_NGEF_PH	Domain

Pfam: PF00017, PF00130, PF00621, PF07653, PF11971, PF22697

UniProt features (42 total): strand 15, modified residue 8, domain 6, helix 4, splice variant 3, sequence conflict 3, chain 1, sequence variant 1, zinc finger region 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
4ROJ	X-RAY DIFFRACTION	1.95
7RNV	X-RAY DIFFRACTION	2.15
7WFY	X-RAY DIFFRACTION	2.45
2DLZ	SOLUTION NMR
2DM1	SOLUTION NMR
2LNW	SOLUTION NMR
2LNX	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P52735-F1	83.80	0.56

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 (8): 172, 576, 583, 626, 769, 771, 142, 159

Function

Pathways and Gene Ontology

Reactome pathways

22 pathways

ID	Pathway
R-HSA-114604	GPVI-mediated activation cascade
R-HSA-193648	NRAGE signals death through JNK
R-HSA-2029482	Regulation of actin dynamics for phagocytic cup formation
R-HSA-2424491	DAP12 signaling
R-HSA-2871796	FCERI mediated MAPK activation
R-HSA-2871809	FCERI mediated Ca+2 mobilization
R-HSA-3928665	EPH-ephrin mediated repulsion of cells
R-HSA-416482	G alpha (12/13) signalling events
R-HSA-4420097	VEGFA-VEGFR2 Pathway
R-HSA-445144	Signal transduction by L1
R-HSA-5218920	VEGFR2 mediated vascular permeability
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9013026	RHOB GTPase cycle
R-HSA-9013106	RHOC GTPase cycle
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9013404	RAC2 GTPase cycle
R-HSA-9013408	RHOG GTPase cycle
R-HSA-9013423	RAC3 GTPase cycle
R-HSA-9664422	FCGR3A-mediated phagocytosis
R-HSA-9748787	Azathioprine ADME
R-HSA-9958810	SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)

MSigDB gene sets: 281 (showing top): PID_BCR_5PATHWAY, REACTOME_INNATE_IMMUNE_SYSTEM, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, GOBP_PLATELET_ACTIVATION, MODULE_45, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_VASCULAR_ENDOTHELIAL_GROWTH_FACTOR_RECEPTOR_SIGNALING_PATHWAY, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, REACTOME_NRAGE_SIGNALS_DEATH_THROUGH_JNK, GOBP_VESICLE_MEDIATED_TRANSPORT, MODULE_453, KEGG_FC_EPSILON_RI_SIGNALING_PATHWAY, GOBP_WOUND_HEALING, SMITH_TERT_TARGETS_DN

GO Biological Process (17): angiogenesis (GO:0001525), immune response-regulating cell surface receptor signaling pathway (GO:0002768), signal transduction (GO:0007165), small GTPase-mediated signal transduction (GO:0007264), regulation of cell size (GO:0008361), cell migration (GO:0016477), lamellipodium assembly (GO:0030032), platelet activation (GO:0030168), Fc-epsilon receptor signaling pathway (GO:0038095), Fc-gamma receptor signaling pathway involved in phagocytosis (GO:0038096), 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), response to xenobiotic stimulus (GO:0009410), cell projection assembly (GO:0030031), intracellular signal transduction (GO:0035556)

GO Molecular Function (6): phosphotyrosine residue binding (GO:0001784), guanyl-nucleotide exchange factor activity (GO:0005085), epidermal growth factor receptor binding (GO:0005154), zinc ion binding (GO:0008270), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (3): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
RHO GTPase cycle	8
Fc epsilon receptor (FCERI) signaling	2
Platelet activation, signaling and aggregation	1
Cell death signalling via NRAGE, NRIF and NADE	1
Fcgamma receptor (FCGR) dependent phagocytosis	1
DAP12 interactions	1
EPH-Ephrin signaling	1
GPCR downstream signalling	1
Signaling by VEGF	1
L1CAM interactions	1
VEGFA-VEGFR2 Pathway	1
Leishmania phagocytosis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular anatomical structure	2
cellular anatomical structure	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
immune response-regulating signaling pathway	1
cell surface receptor signaling pathway	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
intracellular signaling cassette	1
regulation of cellular component size	1
cell motility	1
lamellipodium organization	1
plasma membrane bounded cell projection assembly	1
cell activation	1
blood coagulation	1
Fc receptor signaling pathway	1
Fc receptor mediated stimulatory signaling pathway	1
phagocytosis	1
Fc-gamma receptor signaling pathway	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
response to chemical	1
cellular component assembly	1
cell projection organization	1
signal transduction	1
protein phosphorylated amino acid binding	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
growth factor receptor binding	1
transition metal ion binding	1

Protein interactions and networks

STRING

1538 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VAV2	CTNND1	O60716	962
VAV2	LCP2	Q13094	954
VAV2	SOS1	Q07889	875
VAV2	CDC42	P21181	824
VAV2	GRB2	P29354	815
VAV2	SYK	P43405	804
VAV2	RHOA	P06749	783
VAV2	HCLS1	P14317	764
VAV2	AKT1	P31749	763
VAV2	CTTN	Q14247	763
VAV2	RHOG	P35238	734
VAV2	AKAP13	Q12802	685
VAV2	RABIF	P47224	677
VAV2	RAC1	P15154	669
VAV2	EGFR	P00533	653

IntAct

86 interactions, top by confidence:

A	B	Type	Score
GRB2	EGFR	psi-mi:“MI:0914”(association)	0.980
VAV2	SH3BP2	psi-mi:“MI:0915”(physical association)	0.670
VAV2	SH3BP2	psi-mi:“MI:0914”(association)	0.670
TXNIP	VAV2	psi-mi:“MI:0407”(direct interaction)	0.560
CAV1	PLCG1	psi-mi:“MI:0914”(association)	0.520
VAV2	TOM1L1	psi-mi:“MI:0915”(physical association)	0.510
VAV2	CAV1	psi-mi:“MI:0915”(physical association)	0.500
PRRG4	VAV2	psi-mi:“MI:0407”(direct interaction)	0.440
VAV2	ERBB2	psi-mi:“MI:0407”(direct interaction)	0.440
VAV2	ERBB3	psi-mi:“MI:0407”(direct interaction)	0.440
VAV2	ABI1	psi-mi:“MI:0407”(direct interaction)	0.440
VAV2	AR	psi-mi:“MI:0407”(direct interaction)	0.440
VAV2	GAB1	psi-mi:“MI:0407”(direct interaction)	0.440
VAV2	MET	psi-mi:“MI:0407”(direct interaction)	0.440
SMAD3	FAM83G	psi-mi:“MI:0915”(physical association)	0.400
NEK3	VAV2	psi-mi:“MI:0915”(physical association)	0.400
VAV2	PRLR	psi-mi:“MI:0915”(physical association)	0.400
VAV2	NEK3	psi-mi:“MI:0915”(physical association)	0.400
VAV2	Mbp	psi-mi:“MI:0915”(physical association)	0.400
Ccdc12	PLRG1	psi-mi:“MI:0914”(association)	0.350
Espl1	BDP1	psi-mi:“MI:0914”(association)	0.350
PRKAR2B	SEC16A	psi-mi:“MI:0914”(association)	0.350
DDR1	INPPL1	psi-mi:“MI:0914”(association)	0.350

BioGRID (122): VAV2 (Affinity Capture-Western), CAV1 (Affinity Capture-Western), VAV2 (Reconstituted Complex), VAV2 (Affinity Capture-MS), VAV2 (Co-fractionation), VAV2 (Affinity Capture-MS), VAV2 (Affinity Capture-MS), VAV2 (Affinity Capture-MS), VAV2 (Affinity Capture-MS), VAV2 (Affinity Capture-MS), VAV2 (Affinity Capture-MS), VAV2 (Affinity Capture-RNA), VAV2 (Affinity Capture-RNA), VAV2 (Proximity Label-MS), CTNND1 (Affinity Capture-Western)

ESM2 similar proteins: A2TF48, A5HNF6, A8QMS7, B3SRQ2, B3Y678, B3Y679, B3Y680, B3Y681, B3Y682, B3Y683, B6CJX2, C8BKC7, F1QWA8, I3L5V6, O02697, O88879, P0CI65, P22366, P42338, P48736, P52735, Q13158, Q28DJ2, Q3UR70, Q3V3E1, Q4LBC6, Q599T9, Q5FWM2, Q5XJ85, Q60992, Q61160, Q645M6, Q6AZT7, Q6Y1S1, Q7TNH6, Q7Z494, Q7ZYP6, Q803A6, Q8BGG7, Q8BTI9

Diamond homologs: A1IGU3, A1IGU4, A1IGU5, E7F1U2, P52735, Q55E26, Q5BKC9, Q60992, Q69ZK0, Q6TXD4, Q70Z35, Q80VK6, Q8TCU6, Q9NHV9, Q9NXL2, A1CEK6, A1DFN5, A2QW93, A4FU49, A4RF61, A7A261, A7E3N7, D3ZG83, F1LRS8, O42287, O55043, O60504, O94868, P10569, P19878, P29355, P32793, P38753, P39743, P43603, P49710, P62993, P62994, P80192, P87379

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
CTNND1	up-regulates	VAV2	binding
VAV2	“up-regulates activity”	RHOA	“guanine nucleotide exchange factor”
VAV2	“up-regulates activity”	RAC1	“guanine nucleotide exchange factor”
NTRK2	“up-regulates activity”	VAV2	phosphorylation
SRC	“up-regulates activity”	VAV2	phosphorylation
VAV2	up-regulates	EGFR	binding
VAV2	up-regulates	RAC1	“guanine nucleotide exchange factor”
EGFR	up-regulates	VAV2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 81 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	5	61.5×	2e-06
PI3K events in ERBB2 signaling	5	57.9×	2e-06
Signaling by ERBB2 ECD mutants	5	57.9×	2e-06
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	5	49.2×	4e-06
Signaling by ERBB2 KD Mutants	6	43.8×	2e-06
Signaling by ERBB2 TMD/JMD mutants	5	41.0×	9e-06
Constitutive Signaling by Aberrant PI3K in Cancer	8	17.5×	2e-06
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	8	13.3×	9e-06

GO biological processes:

GO term	Partners	Fold	FDR
epidermal growth factor receptor signaling pathway	8	26.4×	5e-07
phosphatidylinositol 3-kinase/protein kinase B signal transduction	6	16.9×	6e-04
cell surface receptor protein tyrosine kinase signaling pathway	6	13.9×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	125
Likely benign	12
Benign	8

Top pathogenic / likely-pathogenic (0)

SpliceAI

7746 predictions. Top by Δscore:

Variant	Effect	Δscore
9:133768434:CCACT:C	donor_loss	1.0000
9:133768435:CACTC:C	donor_loss	1.0000
9:133768436:ACTCA:A	donor_loss	1.0000
9:133768437:CTCA:C	donor_loss	1.0000
9:133768438:TCACC:T	donor_loss	1.0000
9:133768439:CACCC:C	donor_loss	1.0000
9:133768440:A:T	donor_loss	1.0000
9:133768597:C:CC	acceptor_gain	1.0000
9:133770372:CGTTA:C	donor_loss	1.0000
9:133770373:GTTA:G	donor_loss	1.0000
9:133770374:TTAC:T	donor_loss	1.0000
9:133770375:TACC:T	donor_loss	1.0000
9:133770377:C:CG	donor_loss	1.0000
9:133770379:TGGGG:T	donor_gain	1.0000
9:133770499:CTC:C	acceptor_gain	1.0000
9:133770499:CTCCT:C	acceptor_loss	1.0000
9:133770500:TCC:T	acceptor_loss	1.0000
9:133770502:CT:C	acceptor_loss	1.0000
9:133770503:T:A	acceptor_loss	1.0000
9:133771955:CTA:C	donor_loss	1.0000
9:133771956:TA:T	donor_loss	1.0000
9:133771957:A:AC	donor_gain	1.0000
9:133771958:C:CT	donor_gain	1.0000
9:133771958:C:G	donor_loss	1.0000
9:133774928:CACTT:C	donor_loss	1.0000
9:133774929:ACTTA:A	donor_loss	1.0000
9:133774930:CTTAC:C	donor_loss	1.0000
9:133774931:TTA:T	donor_loss	1.0000
9:133774932:TA:T	donor_loss	1.0000
9:133774933:A:AC	donor_gain	1.0000

AlphaMissense

5865 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:133764099:A:G	F867S	1.000
9:133764105:C:T	G865D	1.000
9:133768458:C:T	G858D	1.000
9:133768459:C:G	G858R	1.000
9:133768465:A:G	W856R	1.000
9:133768465:A:T	W856R	1.000
9:133768563:G:T	A823D	1.000
9:133770437:A:G	L763P	1.000
9:133770437:A:T	L763H	1.000
9:133770449:A:G	L759P	1.000
9:133770457:G:C	F756L	1.000
9:133770457:G:T	F756L	1.000
9:133770458:A:C	F756C	1.000
9:133770458:A:G	F756S	1.000
9:133770459:A:C	F756V	1.000
9:133770459:A:G	F756L	1.000
9:133770459:A:T	F756I	1.000
9:133770470:A:G	L752P	1.000
9:133770470:A:T	L752Q	1.000
9:133770486:A:C	Y747D	1.000
9:133770497:A:G	L743S	1.000
9:133771971:G:C	F737L	1.000
9:133771971:G:T	F737L	1.000
9:133771972:A:G	F737S	1.000
9:133771973:A:G	F737L	1.000
9:133771990:A:C	I731S	1.000
9:133771990:A:T	I731N	1.000
9:133772017:A:T	V722E	1.000
9:133772019:C:A	K721N	1.000
9:133772019:C:G	K721N	1.000

dbSNP variants (sampled 300 via entrez): RS1000007348 (9:133864950 C>A,T), RS1000023000 (9:133832144 C>A,T), RS1000029667 (9:133783705 G>A,T), RS1000038170 (9:133928330 A>C), RS1000040348 (9:133944084 A>G), RS1000045536 (9:133920761 C>A), RS1000065163 (9:133819808 A>C,G), RS1000065209 (9:133973600 C>T), RS1000069202 (9:133849502 C>T), RS1000077449 (9:133800706 C>G), RS1000095169 (9:133849841 T>C), RS1000110477 (9:133880517 G>A), RS1000116345 (9:133891988 GGAGA>G), RS1000123206 (9:133865275 T>C), RS1000150723 (9:133970876 G>A)

Disease associations

OMIM: gene MIM:600428 | disease phenotypes: MIM:191100, MIM:256000, MIM:614202, MIM:614959, MIM:615005

GenCC curated gene-disease

Mondo (5): tuberous sclerosis 1 (MONDO:0008612), Leigh syndrome (MONDO:0009723), Rafiq syndrome (MONDO:0013624), developmental and epileptic encephalopathy, 14 (MONDO:0013989), autosomal dominant nocturnal frontal lobe epilepsy 5 (MONDO:0014002)

Orphanet (5): Epilepsy of infancy with migrating focal seizures (Orphanet:293181), Leigh syndrome (Orphanet:506), Tuberous sclerosis complex (Orphanet:805), Autosomal recessive non-syndromic intellectual disability (Orphanet:88616), Sleep-related hypermotor epilepsy (Orphanet:98784)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST000716_2	Multiple sclerosis	1.000000e-06
GCST001188_2	vWF and FVIII levels	8.000000e-06
GCST004604_53	Hematocrit	2.000000e-10
GCST004615_66	Hemoglobin concentration	4.000000e-10
GCST006366_5	Central corneal thickness	5.000000e-11
GCST007159_28	Corneal astigmatism	4.000000e-07
GCST008758_6	Pre-treatment viral load in HIV-1 infection	9.000000e-16
GCST010083_353	Hemoglobin levels	7.000000e-08
GCST010396_222	Gut microbiota (bacterial taxa, hurdle binary method)	4.000000e-06
GCST90002403_248	Red blood cell count	1.000000e-09

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004630	factor VIII measurement
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0005213	central corneal thickness
EFO:1002040	Corneal astigmatism
EFO:0010125	viral load
EFO:0007874	gut microbiome measurement
EFO:0004305	erythrocyte count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D007888	Leigh Disease	C10.228.140.163.100.412; C16.320.565.189.412; C16.320.565.202.810.444; C18.452.132.100.412; C18.452.648.189.412; C18.452.648.202.810.444; C18.452.660.520
C565346	Tuberous Sclerosis 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, decreases expression, affects cotreatment, increases abundance	3
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
trichostatin A	decreases expression	1
arsenite	affects binding, decreases reaction	1
zinc chromate	decreases expression, increases abundance	1
benzo(e)pyrene	affects methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
aflatoxin B2	affects methylation	1
nickel sulfate	decreases expression, increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
tubeimoside II	decreases reaction, increases phosphorylation	1
abrine	decreases expression	1
bisphenol S	decreases methylation	1
Arsenic Trioxide	decreases response to substance	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	increases expression	1
Caffeine	affects phosphorylation	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Lead	affects splicing	1
Lipopolysaccharides	affects expression, affects response to substance	1
Methapyrilene	affects methylation	1
Methotrexate	decreases expression	1

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2KW	Abcam HeLa VAV2 KO	Cancer cell line	Female
CVCL_TX31	HAP1 VAV2 (-) 1	Cancer cell line	Male
CVCL_TX32	HAP1 VAV2 (-) 2	Cancer cell line	Male
CVCL_TX33	HAP1 VAV2 (-) 3	Cancer cell line	Male
CVCL_TX34	HAP1 VAV2 (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02201212	PHASE2	COMPLETED	Everolimus for Cancer With TSC1 or TSC2 Mutation
NCT05103358	PHASE2	ACTIVE_NOT_RECRUITING	Phase 2 Basket Trial of Nab-sirolimus in Patients With Malignant Solid Tumors With Pathogenic Alterations in TSC1/TSC2 Genes (PRECISION 1)
NCT01721733	PHASE2	COMPLETED	Safety and Efficacy Study of EPI-743 in Children With Leigh Syndrome
NCT02352896	PHASE2	COMPLETED	Long-Term Safety and Efficacy Evaluation of EPI-743 in Children With Leigh Syndrome
NCT03747328	PHASE2	WITHDRAWN	ABI-009 (Nab-sirolimus) in Patients With Genetically-confirmed Leigh or Leigh-like Syndrome
NCT06843811	PHASE2	ENROLLING_BY_INVITATION	Sirolimus for Leigh Syndrome
NCT06990984	PHASE2	NOT_YET_RECRUITING	A Dose-ranging Study of TTI-0102 in Adults and Children With Leigh Syndrome Spectrum (LSS)
NCT07600736	PHASE2	RECRUITING	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Clinical Activity of ABS-1230 in Pediatric Participants With KCNT1-related Epilepsy
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT07156201	PHASE1	RECRUITING	A Study to Investigate the Safety, Tolerability, and Pharmacokinetics of ABS-1230 Given Orally Compared With Placebo in Healthy Participants Aged 18 to 55 Years
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT03817515	Not specified	APPROVED_FOR_MARKETING	Expanded Access for ABI-009 in Patients With Advanced PEComa and Patients With a Malignancy With Relevant Genetic Mutations or mTOR Pathway Activation
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01780168	Not specified	RECRUITING	The NIH MINI Study: Metabolism, Infection, and Immunity in Inborn Errors of Metabolism
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01803906	Not specified	ENROLLING_BY_INVITATION	Tissue Sample Study for Mitochondrial Disorders
NCT03137355	Not specified	RECRUITING	The International Registry for Leigh Syndrome
NCT05277363	Not specified	WITHDRAWN	A Study of the Natural Course of SURF1 Deficiency
NCT05554835	Not specified	RECRUITING	Global Registry and Natural History Study for Mitochondrial Disorders
NCT06967831	Not specified	RECRUITING	Drug Repurposing for Mitochondrial Disorders Using iPSCs Derived Neural Cells
NCT04924153	Not specified	COMPLETED	A Natural History Study of Participants With Potassium Sodium-Activated Channel Subfamily T Member 1 (KCNT1)-Related Epilepsy