SH3PXD2A

Summary

SH3PXD2A (SH3 and PX domains 2A, HGNC:23664) is a protein-coding gene on chromosome 10q24.33, encoding SH3 and PX domain-containing protein 2A (Q5TCZ1). Adapter protein involved in invadopodia and podosome formation, extracellular matrix degradation and invasiveness of some cancer cells.

Predicted to enable superoxide-generating NADPH oxidase activator activity. Involved in osteoclast fusion and superoxide metabolic process. Located in cytosol and podosome.

Source: NCBI Gene 9644 — RefSeq curated summary.

At a glance

• GWAS associations: 55
• Clinical variants (ClinVar): 194 total
• MANE Select transcript: NM_001394015

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23664
Approved symbol	SH3PXD2A
Name	SH3 and PX domains 2A
Location	10q24.33
Locus type	gene with protein product
Status	Approved
Aliases	FISH, KIAA0418
Ensembl gene	ENSG00000107957
Ensembl biotype	protein_coding
OMIM	619455
Entrez	9644

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding_CDS_not_defined, 3 protein_coding

ENST00000315994, ENST00000355946, ENST00000369774, ENST00000420222, ENST00000687380, ENST00000691105, ENST00000692756

RefSeq mRNA: 11 — MANE Select: NM_001394015 NM_001365079, NM_001394015, NM_001394016, NM_001394017, NM_001394018, NM_001394019, NM_001394020, NM_001394021, NM_001394022, NM_001394023, NM_014631

CCDS: CCDS31278, CCDS91343

Canonical transcript exons

ENST00000369774 — 15 exons

Exon	Start	End
ENSE00000811670	103724270	103724361
ENSE00000987725	103622470	103622553
ENSE00001274601	103735732	103735808
ENSE00001385766	103801282	103801362
ENSE00001611723	103855195	103855576
ENSE00001939716	103594027	103603789
ENSE00002521677	103767094	103767169
ENSE00003550659	103668608	103668652
ENSE00003611862	103693028	103693056
ENSE00003630260	103611581	103611630
ENSE00003632199	103605798	103605917
ENSE00003659339	103612853	103613190
ENSE00003669979	103627089	103627202
ENSE00003670354	103660983	103661114
ENSE00003680026	103617197	103617314

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 97.57.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 32.0761 / max 355.6517, expressed in 1690 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
111239	11.6362	1259
111240	7.2692	1194
111257	3.4856	1102
111245	2.9545	688
111255	2.0281	789
111248	1.5153	353
111256	1.5020	656
111249	1.1382	411
111247	0.3915	147
111258	0.1014	29

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	97.57	gold quality
stromal cell of endometrium	CL:0002255	96.59	gold quality
trigeminal ganglion	UBERON:0001675	96.59	gold quality
tibia	UBERON:0000979	95.59	gold quality
dorsal root ganglion	UBERON:0000044	95.05	gold quality
skin of hip	UBERON:0001554	94.96	gold quality
inferior vagus X ganglion	UBERON:0005363	94.75	gold quality
upper leg skin	UBERON:0004262	94.33	gold quality
nipple	UBERON:0002030	93.95	gold quality
tendon of biceps brachii	UBERON:0008188	93.95	gold quality
subthalamic nucleus	UBERON:0001906	93.51	gold quality
mammalian vulva	UBERON:0000997	93.43	gold quality
endocervix	UBERON:0000458	93.13	gold quality
pharyngeal mucosa	UBERON:0000355	92.95	gold quality
tibial nerve	UBERON:0001323	92.92	gold quality
lower esophagus mucosa	UBERON:0035834	92.87	gold quality
saphenous vein	UBERON:0007318	92.60	gold quality
ectocervix	UBERON:0012249	91.92	gold quality
penis	UBERON:0000989	91.65	gold quality
oral cavity	UBERON:0000167	91.61	gold quality
myometrium	UBERON:0001296	91.61	gold quality
urethra	UBERON:0000057	91.23	gold quality
body of uterus	UBERON:0009853	90.96	gold quality
dorsal plus ventral thalamus	UBERON:0001897	90.66	gold quality
ventral tegmental area	UBERON:0002691	90.65	gold quality
colonic epithelium	UBERON:0000397	90.52	gold quality
visceral pleura	UBERON:0002401	90.46	gold quality
seminal vesicle	UBERON:0000998	90.44	gold quality
left uterine tube	UBERON:0001303	90.21	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	90.19	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	38.37
E-ANND-3	yes	8.36
E-CURD-114	no	111.31

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): IRF3, SP1

miRNA regulators (miRDB)

545 targeting SH3PXD2A, 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-7110-3P	100.00	73.18	2486
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012

Literature-anchored findings (GeneRIF, showing 35)

• Tks5/Fish appears to be required for podosome formation, for degradation of the extracellular matrix, and for invasion of some cancer cells (PMID:15710328)
• The most significant statistical interaction is between rs3740473, a synonymous single nucleotide polymorphism (SNP) in SH3MD1 and rs11244787, an intronic SNP in ADAM12 (effect size = 2.1 for interaction term, P = 0.006). (PMID:17440933)
• The tandem SH3A and SH3B domains of Tks5 constitute a versatile module for the implementation of isoform-specific protein-protein interactions. (PMID:19464300)
• Results demonstrate that Tks5 plays a central role in the recruitment of AFAP-110, p190RhoGAP, and cortactin to drive podosome formation. (PMID:19540230)
• Tks proteins selectively support Nox1 and Nox3 (and not Nox2 and Nox4) activity in reconstituted cellular systems and interact with the NoxA1 activator protein through an Src homology 3 domain-mediated interaction (PMID:19755710)
• Our data do not support the existence of an interaction between rs11244787 in ADAM12 and rs3740473 in SH3PXD2A in terms of the risk of AD. (PMID:19837132)
• Tks4 and Tks5 directly bind to NoxA1. The integrity of the N-terminal PRR of NoxA1 is essential for this direct interaction with the Tks proteins. (PMID:20609497)
• Tks5 or cortactin occurred in all grades of tumours and expression of Tks5, but not cortactin, was associated with significantly reduced patient survival among glioma patients (PMID:22249020)
• Tks5, a master regulator of invadopodia in cancer cells, is crucial for osteoclast fusion downstream of phosphoinositide 3-kinase and Src. (PMID:22584907)
• Genes including LEP and SH3PXD2A were differentially expressed (p<0.05 and fold change >1.5) in pre-eclampsia placentas. (PMID:23544093)
• high Tks5long and low Tks5short expressions in human lung adenocarcinomas correlated with metastatic disease and predicted worse survival of early stage patients (PMID:23873940)
• Src-dependent Tks5 phosphorylation regulates invadopodia-associated invasion in prostate cancer cells. (PMID:24174371)
• Tks5 is needed for breast carcinoma cell invadopodium precursor stabilization, where the phox homology (PX) domain of Tks5 interacts with PI(3,4)P2. SHIP2 arrival at the invadopodium precursor coincides with the onset of PI(3,4)P2 accumulation. (PMID:24206842)
• Results show that TKS5 is highly expressed in many cancer types with strong correlation with increased metastatic events and a poorer prognosis suggesting a clinical importance. (PMID:24993883)
• Inhibiting the function of Tks5 both reduced extracellular matrix degradation in vitro and disrupted motoneuron axons from exiting the spinal cord and extending into the periphery. (PMID:25564649)
• establishes an important role for Tks5 in tumor growth in vivo, and suggests that invadopodia may play broad roles in tumor progression (PMID:25826475)
• TKS5 and MYLK represent two mediators of invasive behavior of cancer cells that are regulated by the ZEB1/miR-200 feedback loop (PMID:26334100)
• Results suggest that Tks5, similar to XB130, plays a role in cell proliferation and cell survival and that the interaction between XB130 and Tks5 appears to be critical for regulation of Src-mediated cellular homeostasis. (PMID:26446840)
• This is the first study that identifies a new Rab40b-Tks5- and miR-204-dependent invadopodia transport pathway that regulates MMP2 and MMP9 secretion, and extracellular matrix remodeling during cancer progression. (PMID:27789576)
• Suggest the importance of Tks adaptor proteins in melanoma growth and metastasis in vivo is likely via functional invadopodia formation. (PMID:27802184)
• Our results suggest that dissociation between XB130 and Tks5 may facilitate lateral cell migration via XB130/Rac1, and vertical cell migration via Tks5/Cdc42. These molecular mechanisms will help our understanding of airway epithelial repair and regeneration. (PMID:27835612)
• This is the first study that identifies a new Rab40b-Tks5- and miR-204-dependent invadopodia transport pathway that regulates MMP2 and MMP9 secretion, and extracellular matrix remodeling during cancer progression. (PMID:27909076)
• Results show that the interaction between Girdin and Tks5 might be important for Tks5 phosphorylation in HCC cells. (PMID:28390157)
• Rheumatoid arthritis T cells abundantly express the podosome scaffolding protein TKS5, which enables them to form tissue-invasive membrane structures. TKS5 overexpression was regulated by the intracellular metabolic environment of RA T cells-specifically, by reduced glycolytic flux that led to deficiencies in ATP and pyruvate. (PMID:28737753)
• TKS5 is expressed in human pancreatic adenocarcinoma lines. TKS5 localizes at mature and immature invadopodia in pancreatic cancer cells. Pancreatic cancer cells depend on TKS5 for invadopodia formation and function. (PMID:30439350)
• The present GWAS was the first to implicate SH3PXD2A in non-syndromic cleft formation in humans. In summary, although performed in a relatively small sample, the present GWAS generated novel insights into nsCL/P etiology. (PMID:31817908)
• in the invadopodia-competent Src-3T3 model system, mutations in any one of the first three SH3 domains had a dominant negative effect that largely eliminated the presence of invadopodia, inhibited gelatin degradation activity, and redistributed both Src, cortactin, and Tks5 to what are likely endosomal compartments (PMID:31999741)
• Intersection of TKS5 and FGD1/CDC42 signaling cascades directs the formation of invadopodia. (PMID:32673397)
• Functional Role of the L396R Mutation of Tks5 Identified by an Exome-Wide Association Study in Atrial Fibrillation. (PMID:33087629)
• Serine-Threonine Kinase TAO3-Mediated Trafficking of Endosomes Containing the Invadopodia Scaffold TKS5alpha Promotes Cancer Invasion and Tumor Growth. (PMID:33414172)
• STAT3/SH3PXD2A-AS1/miR-125b/STAT3 positive feedback loop affects psoriasis pathogenesis via regulating human keratinocyte proliferation. (PMID:33994260)
• The clinicopathologic significance of Tks5 expression of peritoneal mesothelial cells in gastric cancer patients. (PMID:34255789)
• Tks5 Regulates Synaptic Podosome Formation and Stabilization of the Postsynaptic Machinery at the Neuromuscular Junction. (PMID:34769479)
• Spontaneous malignant transformation of trigeminal schwannoma: consideration of responsible gene alterations for tumorigenesis-a case report. (PMID:37515639)
• A MAP1B-cortactin-Tks5 axis regulates TNBC invasion and tumorigenesis. (PMID:38353696)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	sh3pxd2aa	ENSDARG00000060148
danio_rerio	sh3pxd2ab	ENSDARG00000061758
mus_musculus	Sh3pxd2a	ENSMUSG00000053617
rattus_norvegicus	Sh3pxd2a	ENSRNOG00000089802

Paralogs (3): NCF1 (ENSG00000158517), SH3PXD2B (ENSG00000174705), NOXO1 (ENSG00000196408)

Protein

Protein identifiers

SH3 and PX domain-containing protein 2A — Q5TCZ1 (reviewed: Q5TCZ1)

Alternative names: Adapter protein TKS5, Five SH3 domain-containing protein, SH3 multiple domains protein 1, Tyrosine kinase substrate with five SH3 domains

All UniProt accessions (2): Q5TCZ1, A0A8I5KQW5

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein involved in invadopodia and podosome formation, extracellular matrix degradation and invasiveness of some cancer cells. Binds matrix metalloproteinases (ADAMs), NADPH oxidases (NOXs) and phosphoinositides. Acts as an organizer protein that allows NOX1- or NOX3-dependent reactive oxygen species (ROS) generation and ROS localization. In association with ADAM12, mediates the neurotoxic effect of amyloid-beta peptide.

Subunit / interactions. Interacts (via N-terminus) with CYBA. Interacts with ADAM12, ADAM15 and ADAM19. Interacts with NOXO1. Interacts (via SH3 domains) with NOXA1. Interacts with FASLG. Interacts (via PX domain) with RAB40B (GTP-bound); interaction promotes invadopodia-mediated extracellular matrix degradation.

Subcellular location. Cytoplasm. Cell projection. Podosome.

Tissue specificity. Found in several cancer cell lines, particularly invasive breast carcinomas and melanomas.

Post-translational modifications. Tyrosine phosphorylated by SRC. Phosphorylation plays a regulatory role in the protein localization. The intramolecular interaction of the PX domain with the third SH3 domain maintains the protein in the cytoplasm and phosphorylation disrupts this interaction, resulting in the redistribution of the protein from cytoplasm to the perimembrane region. Phosphorylated on serine upon DNA damage, probably by ATM or ATR.

Domain organisation. The PX domain is required for podosome localization because of its ability to bind phosphatidylinositol 3-phosphate (PtdIns(3)P) and phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2) and, to a lesser extent, phosphatidylinositol 4-phosphate (PtdIns(4)P), phosphatidylinositol 5-phosphate (PtdIns(5)P), and phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2). Binds to the third intramolecular SH3 domain. Required for interaction with RAB40B. The fifth SH3 domain mediates binding with ADAM12, ADAM15 and ADAM19.

Miscellaneous. Gene prediction based on similarity to mouse ortholog and partial transcript data.

Similarity. Belongs to the SH3PXD2 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q5TCZ1-1	1	yes
Q5TCZ1-2	2
Q5TCZ1-3	3

RefSeq proteins (7): NP_001380944, NP_001380945, NP_001380948, NP_001380949, NP_001380950, NP_001380952, NP_055446 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR001683	PX_dom	Domain
IPR035449	SH3PXD2A_SH3_3	Domain
IPR035450	SH3PXD2A_SH3_1	Domain
IPR035452	SH3PXD2A_SH3_2	Domain
IPR035453	SH3PXD2A_SH3_4	Domain
IPR035454	SH3PXD2A_SH3_5	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036871	PX_dom_sf	Homologous_superfamily
IPR037961	SH3PXD2_PX	Domain
IPR051228	NADPH_Oxidase/PX-Domain	Family

Pfam: PF00018, PF00787, PF07653

UniProt features (68 total): strand 20, modified residue 16, compositionally biased region 7, domain 6, region of interest 5, sequence variant 3, mutagenesis site 3, helix 3, splice variant 2, chain 1, coiled-coil region 1, turn 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
2DNU	SOLUTION NMR
2EGA	SOLUTION NMR
2EGC	SOLUTION NMR
2EKH	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5TCZ1-F1	57.73	0.22

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 (16): 256, 406, 421, 547, 567, 593, 644, 731, 767, 769, 819, 829, 1002, 1016, 1017, 1038

Mutagenesis-validated functional residues (3):

Position	Phenotype
24	loss of interaction with rab40b.
42	loss of binding to (ptdins(3)p) and (ptdins(3,4)p2).
93	loss of binding to (ptdins(3)p) and (ptdins(3,4)p2).

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-8941237	Invadopodia formation
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-1474244	Extracellular matrix organization
R-HSA-162582	Signal Transduction
R-HSA-194315	Signaling by Rho GTPases
R-HSA-9012999	RHO GTPase cycle
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 343 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, TGCACTT_MIR519C_MIR519B_MIR519A, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, GOBP_SUPEROXIDE_METABOLIC_PROCESS, GOBP_MYELOID_LEUKOCYTE_DIFFERENTIATION, CAGGTCC_MIR492, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, GTGCCTT_MIR506, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, GOBP_SUPEROXIDE_ANION_GENERATION

GO Biological Process (5): in utero embryonic development (GO:0001701), superoxide metabolic process (GO:0006801), superoxide anion generation (GO:0042554), osteoclast fusion (GO:0072675), reactive oxygen species metabolic process (GO:0072593)

GO Molecular Function (9): protease binding (GO:0002020), phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), phosphatidylinositol-5-phosphate binding (GO:0010314), superoxide-generating NADPH oxidase activator activity (GO:0016176), phosphatidylinositol-3-phosphate binding (GO:0032266), phosphatidylinositol-3,4-bisphosphate binding (GO:0043325), phosphatidylinositol-4-phosphate binding (GO:0070273), protein binding (GO:0005515), phosphatidylinositol binding (GO:0035091)

GO Cellular Component (6): podosome (GO:0002102), cytoplasm (GO:0005737), cytosol (GO:0005829), ciliary transition zone (GO:0035869), cell projection (GO:0042995), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Extracellular matrix organization	1
RHO GTPase cycle	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Signaling by Rho GTPases	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
phosphatidylinositol phosphate binding	4
cellular anatomical structure	4
anion binding	3
phosphatidylinositol bisphosphate binding	2
chordate embryonic development	1
reactive oxygen species metabolic process	1
superoxide metabolic process	1
syncytium formation by cell-cell fusion	1
multinuclear osteoclast differentiation	1
metabolic process	1
enzyme binding	1
enzyme activator activity	1
superoxide-generating NADPH oxidase activity	1
binding	1
actin-based cell projection	1
intracellular anatomical structure	1
cytoplasm	1
cilium	1
cell junction	1

Protein interactions and networks

STRING

1720 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SH3PXD2A	WASL	O00401	992
SH3PXD2A	HCLS1	P14317	971
SH3PXD2A	CTTN	Q14247	971
SH3PXD2A	GRB2	P29354	954
SH3PXD2A	WAS	P42768	917
SH3PXD2A	ADAM12	O43184	896
SH3PXD2A	ITGB1	P05556	886
SH3PXD2A	SRC	P12931	841
SH3PXD2A	CFL2	Q9Y281	827
SH3PXD2A	CFL1	P23528	827
SH3PXD2A	NCK1	P16333	793
SH3PXD2A	MMP14	P50281	743
SH3PXD2A	NOX3	Q9HBY0	738
SH3PXD2A	CYBA	P13498	735
SH3PXD2A	NOXA1	Q86UR1	723

IntAct

137 interactions, top by confidence:

A	B	Type	Score
YWHAQ	WDR62	psi-mi:“MI:0914”(association)	0.830
YWHAB	PIK3C2A	psi-mi:“MI:0914”(association)	0.800
ADAM15	SH3PXD2A	psi-mi:“MI:0407”(direct interaction)	0.710
SH3PXD2A	ADAM15	psi-mi:“MI:0915”(physical association)	0.710
ADAM15	SH3PXD2A	psi-mi:“MI:0915”(physical association)	0.710
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
NCK2	SH3PXD2B	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
YWHAB	BLTP3B	psi-mi:“MI:0914”(association)	0.610
ADAM19	SH3PXD2A	psi-mi:“MI:0407”(direct interaction)	0.590
YWHAE	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
YWHAZ	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
PRKAB2	PRKAB2	psi-mi:“MI:0914”(association)	0.550
YWHAQ	IGLC7	psi-mi:“MI:0914”(association)	0.530
GRB2	SH3PXD2B	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
ZNF764	SH3PXD2B	psi-mi:“MI:0914”(association)	0.530
SH3PXD2A	FGD1	psi-mi:“MI:0914”(association)	0.530
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
ADAM12	SH3PXD2A	psi-mi:“MI:0407”(direct interaction)	0.440
FASLG	SH3PXD2A	psi-mi:“MI:0407”(direct interaction)	0.440
SH3PXD2A	SOS1	psi-mi:“MI:0407”(direct interaction)	0.440
SH3PXD2A	Dnm1	psi-mi:“MI:0407”(direct interaction)	0.440
SVIL	SH3PXD2A	psi-mi:“MI:0915”(physical association)	0.440
SVIL	SH3PXD2A	psi-mi:“MI:0403”(colocalization)	0.440

BioGRID (184): SH3PXD2A (Affinity Capture-MS), SH3PXD2A (Affinity Capture-MS), SH3PXD2A (Affinity Capture-MS), SH3PXD2A (Affinity Capture-MS), SH3PXD2A (Affinity Capture-MS), SH3PXD2A (Affinity Capture-MS), SH3PXD2A (Affinity Capture-MS), SH3PXD2A (Affinity Capture-MS), KCTD3 (Affinity Capture-MS), KIF13B (Affinity Capture-MS), ZBTB21 (Affinity Capture-MS), SH3PXD2A (Affinity Capture-MS), GIGYF1 (Affinity Capture-MS), LRFN1 (Affinity Capture-MS), DENND1A (Affinity Capture-MS)

ESM2 similar proteins: A0JNJ1, A5PMU4, A6QQV9, A7E3S4, D4AB98, F7EL49, P15056, P34908, P59672, P97306, Q04982, Q13905, Q15678, Q16825, Q5F488, Q5TCQ9, Q5TCZ1, Q62130, Q62136, Q62728, Q6DD51, Q6H8Q1, Q6KC51, Q6P9K8, Q6ZMT1, Q80T23, Q80YS6, Q812E4, Q8BL65, Q8BN59, Q8BZ71, Q8BZI0, Q8N556, Q8R1B0, Q8TDW5, Q8TED9, Q8TEW8, Q8VH46, Q8VHK2, Q8WXD9

Diamond homologs: A1X283, A1ZAY1, A2AAY5, A4RE77, A6NI72, A6SED8, A7EK16, A8MVU1, A8N2Y6, A8PWF6, B0CRJ3, F1M707, O00443, O43586, O77774, O89032, P0CP00, P0CP01, P10569, P14598, P29366, P62484, P97814, Q09014, Q1LYG0, Q2HDI2, Q2KJB5, Q54FG5, Q5I0D6, Q5RAY1, Q5TCX8, Q5TCZ1, Q61194, Q6WKZ7, Q7Z8J6, Q8IVI9, Q8VDG6, Q9NYB9, Q9QX73, Q9Y7Z8

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
SH3PXD2A	“up-regulates activity”	NOXA1	binding
SRC	“up-regulates activity”	SH3PXD2A	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 119 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
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	9	74.6×	3e-13
Activation of BAD and translocation to mitochondria	7	65.8×	7e-10
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	58.0×	2e-09
Activation of BH3-only proteins	7	42.9×	9e-09
RHO GTPases activate PKNs	8	31.3×	9e-09
Intrinsic Pathway for Apoptosis	7	25.3×	3e-07
FOXO-mediated transcription	5	20.7×	6e-05
RHOU GTPase cycle	5	17.2×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	6	19.8×	2e-04
epidermal growth factor receptor signaling pathway	5	11.2×	8e-03
intracellular protein localization	9	8.5×	2e-04
regulation of small GTPase mediated signal transduction	6	7.8×	9e-03
protein phosphorylation	11	6.7×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	168
Likely benign	5
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

4224 predictions. Top by Δscore:

Variant	Effect	Δscore
10:103605301:T:TA	donor_gain	1.0000
10:103611580:CCAGG:C	donor_gain	1.0000
10:103612851:A:AC	donor_gain	1.0000
10:103612852:C:CC	donor_gain	1.0000
10:103612852:CTGAT:C	donor_gain	1.0000
10:103612919:T:TA	donor_gain	1.0000
10:103612985:T:TA	donor_gain	1.0000
10:103613004:ATGGC:A	donor_gain	1.0000
10:103622597:G:T	acceptor_gain	1.0000
10:103627083:CCTCA:C	donor_loss	1.0000
10:103627084:CTCAC:C	donor_loss	1.0000
10:103627085:TCA:T	donor_loss	1.0000
10:103627086:CA:C	donor_loss	1.0000
10:103627087:A:AT	donor_loss	1.0000
10:103627088:C:CT	donor_loss	1.0000
10:103627088:CCTT:C	donor_gain	1.0000
10:103627198:CCAGC:C	acceptor_gain	1.0000
10:103627199:CAGC:C	acceptor_gain	1.0000
10:103627199:CAGCC:C	acceptor_gain	1.0000
10:103627200:AGC:A	acceptor_gain	1.0000
10:103627200:AGCCT:A	acceptor_loss	1.0000
10:103627201:GC:G	acceptor_gain	1.0000
10:103627201:GCCT:G	acceptor_loss	1.0000
10:103627202:CC:C	acceptor_gain	1.0000
10:103627203:C:CA	acceptor_loss	1.0000
10:103627203:C:CC	acceptor_gain	1.0000
10:103627204:T:C	acceptor_loss	1.0000
10:103660976:CACT:C	donor_loss	1.0000
10:103660977:ACTC:A	donor_loss	1.0000
10:103660978:CTCA:C	donor_loss	1.0000

AlphaMissense

7341 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:103603713:A:T	I502N	1.000
10:103603728:G:T	A497D	1.000
10:103603730:C:A	W496C	1.000
10:103603730:C:G	W496C	1.000
10:103603732:A:G	W496R	1.000
10:103603732:A:T	W496R	1.000
10:103603735:C:G	G495R	1.000
10:103603762:A:G	W486R	1.000
10:103603762:A:T	W486R	1.000
10:103603763:C:A	W485C	1.000
10:103603763:C:G	W485C	1.000
10:103603765:A:G	W485R	1.000
10:103603765:A:T	W485R	1.000
10:103605820:A:G	F469S	1.000
10:103605849:G:C	F459L	1.000
10:103605849:G:T	F459L	1.000
10:103605850:A:G	F459S	1.000
10:103605851:A:G	F459L	1.000
10:103613152:A:G	L320P	1.000
10:103627148:A:G	L220P	1.000
10:103627160:G:T	P216H	1.000
10:103627163:A:T	V215D	1.000
10:103627167:A:G	W214R	1.000
10:103627167:A:T	W214R	1.000
10:103627170:C:G	G213R	1.000
10:103627190:A:T	V206E	1.000
10:103627197:A:G	W204R	1.000
10:103627197:A:T	W204R	1.000
10:103627200:A:G	W203R	1.000
10:103627200:A:T	W203R	1.000

dbSNP variants (sampled 300 via entrez): RS1000018007 (10:103815123 C>T), RS1000022506 (10:103684424 T>C), RS1000034252 (10:103719389 T>C), RS1000057761 (10:103857178 C>T), RS1000067259 (10:103684124 G>A,T), RS1000076844 (10:103835842 C>T), RS1000083569 (10:103690704 A>C,G), RS1000098008 (10:103601664 G>A), RS1000102120 (10:103793476 A>C), RS1000105115 (10:103623416 C>A), RS1000112374 (10:103599916 C>A,T), RS1000113156 (10:103620414 T>G), RS1000113717 (10:103667183 C>G,T), RS1000116133 (10:103610644 G>A), RS1000119209 (10:103837635 C>G)

Disease associations

OMIM: gene MIM:619455 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

55 associations (top):

Study	Trait	p-value
GCST002875_131	Diisocyanate-induced asthma	1.000000e-06
GCST002875_3	Diisocyanate-induced asthma	1.000000e-06
GCST002932_10	Manganese levels	6.000000e-06
GCST003013_18	White matter hyperintensity burden	2.000000e-08
GCST003013_19	White matter hyperintensity burden	2.000000e-08
GCST003013_4	White matter hyperintensity burden	2.000000e-08
GCST003013_5	White matter hyperintensity burden	3.000000e-09
GCST003061_5	Cutaneous malignant melanoma	2.000000e-09
GCST004296_2	Atrial fibrillation	6.000000e-09
GCST004297_7	Atrial fibrillation	2.000000e-11
GCST004373_9	Atrial fibrillation	2.000000e-11
GCST005306_3	Atrial fibrillation	7.000000e-07
GCST005580_169	Intraocular pressure	1.000000e-08
GCST006061_12	Atrial fibrillation	1.000000e-40
GCST007045_34	PR interval	6.000000e-18
GCST007656_1	Chronic obstructive pulmonary disease or resting heart rate (pleiotropy)	2.000000e-10
GCST007843_18	Rheumatoid arthritis	6.000000e-11
GCST008161_93	Waist circumference adjusted for body mass index	3.000000e-06
GCST010002_298	Refractive error	3.000000e-22
GCST010101_10	White matter hyperintensities	1.000000e-14
GCST010321_127	PR interval	5.000000e-52
GCST010703_45	Brain morphology (MOSTest)	1.000000e-08
GCST010726_43	Periventricular white matter hyperintensities	2.000000e-11
GCST010796_2717	Electrocardiogram morphology (amplitude at temporal datapoints)	9.000000e-16
GCST010796_2718	Electrocardiogram morphology (amplitude at temporal datapoints)	8.000000e-10
GCST010796_2719	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-11
GCST010796_2720	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-12
GCST010796_2721	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-12
GCST010796_2722	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-13
GCST010796_2723	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-14

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0006995	response to diisocyanate
EFO:0005665	white matter hyperintensity measurement
EFO:0004695	intraocular pressure measurement
EFO:0004462	PR interval
EFO:0007789	BMI-adjusted waist circumference
EFO:0004346	neuroimaging measurement
EFO:0004327	electrocardiography

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases methylation, affects methylation	8
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	4
trichostatin A	affects cotreatment, increases expression	3
bisphenol S	affects cotreatment, decreases expression, decreases methylation, increases expression	3
Estradiol	affects cotreatment, increases expression, decreases expression	3
Tretinoin	decreases expression, increases expression	3
bisphenol A	affects cotreatment, increases methylation, decreases expression, affects methylation	2
sodium arsenite	decreases expression, increases methylation	2
Calcitriol	decreases expression, increases expression	2
Aflatoxin B1	increases methylation, affects expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment, increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	increases expression	1
afuresertib	increases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
dicrotophos	increases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
sulforaphane	decreases expression, increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	affects methylation	1
aflatoxin B2	affects methylation	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
dorsomorphin	increases expression, affects cotreatment	1

Clinical trials (associated diseases)

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