AGAP2

Summary

AGAP2 (ArfGAP with GTPase domain, ankyrin repeat and PH domain 2, HGNC:16921) is a protein-coding gene on chromosome 12q14.1, encoding Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 2 (Q99490). GTPase-activating protein (GAP) for ARF1 and ARF5, which also shows strong GTPase activity. It is a selective cancer dependency (DepMap: 12.3% of cell lines).

The protein encoded by this gene belongs to the centaurin gamma-like family. It mediates anti-apoptotic effects of nerve growth factor by activating nuclear phosphoinositide 3-kinase. It is overexpressed in cancer cells, and promotes cancer cell invasion. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.

Source: NCBI Gene 116986 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 182 total — 3 pathogenic, 2 likely-pathogenic
• Cancer dependency (DepMap): dependent in 12.3% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001122772

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16921
Approved symbol	AGAP2
Name	ArfGAP with GTPase domain, ankyrin repeat and PH domain 2
Location	12q14.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000135439
Ensembl biotype	protein_coding
OMIM	605476
Entrez	116986

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000257897, ENST00000328568, ENST00000547588, ENST00000549129, ENST00000943666

RefSeq mRNA: 2 — MANE Select: NM_001122772 NM_001122772, NM_014770

CCDS: CCDS44932, CCDS8951

Canonical transcript exons

ENST00000547588 — 19 exons

Exon	Start	End
ENSE00000920455	57735369	57735427
ENSE00000920456	57734592	57734679
ENSE00000920457	57734319	57734404
ENSE00000920458	57734026	57734173
ENSE00000920459	57732845	57732979
ENSE00000920460	57732403	57732512
ENSE00000920461	57731809	57731967
ENSE00000920462	57731556	57731642
ENSE00000920463	57731366	57731470
ENSE00000920464	57730791	57730953
ENSE00000920465	57730495	57730614
ENSE00000920466	57729639	57729767
ENSE00000920467	57727937	57728085
ENSE00000920468	57727681	57727771
ENSE00000920469	57727360	57727582
ENSE00000920470	57726974	57727229
ENSE00001294677	57728318	57728377
ENSE00001313098	57737079	57738742
ENSE00003928303	57725197	57726794

Expression profiles

Bgee: expression breadth ubiquitous, 212 present calls, max score 98.87.

FANTOM5 (CAGE): breadth broad, TPM avg 2.7852 / max 94.7064, expressed in 500 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
131741	2.2517	387
131733	0.1608	68
131742	0.1161	68
131740	0.1129	50
131734	0.1104	54
131732	0.0199	10
131729	0.0133	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	98.87	gold quality
cerebellar hemisphere	UBERON:0002245	98.56	gold quality
cerebellar cortex	UBERON:0002129	98.48	gold quality
right frontal lobe	UBERON:0002810	98.15	gold quality
cingulate cortex	UBERON:0003027	96.97	gold quality
anterior cingulate cortex	UBERON:0009835	96.94	gold quality
cerebellum	UBERON:0002037	96.84	gold quality
nucleus accumbens	UBERON:0001882	96.76	gold quality
amygdala	UBERON:0001876	96.49	gold quality
prefrontal cortex	UBERON:0000451	96.27	gold quality
cortical plate	UBERON:0005343	96.01	gold quality
caudate nucleus	UBERON:0001873	95.67	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.57	gold quality
putamen	UBERON:0001874	95.37	gold quality
frontal pole	UBERON:0002795	94.86	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.60	gold quality
paraflocculus	UBERON:0005351	94.01	gold quality
neocortex	UBERON:0001950	93.84	gold quality
frontal cortex	UBERON:0001870	93.79	gold quality
middle frontal gyrus	UBERON:0002702	93.74	gold quality
telencephalon	UBERON:0001893	92.76	gold quality
cerebral cortex	UBERON:0000956	92.33	gold quality
Ammon’s horn	UBERON:0001954	91.93	gold quality
apex of heart	UBERON:0002098	91.39	gold quality
forebrain	UBERON:0001890	90.81	gold quality
brain	UBERON:0000955	90.77	gold quality
temporal lobe	UBERON:0001871	90.54	gold quality
central nervous system	UBERON:0001017	90.35	gold quality
granulocyte	CL:0000094	89.77	gold quality
Brodmann (1909) area 10	UBERON:0013541	89.71	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.37
E-MTAB-4850	no	556.42

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

62 targeting AGAP2, 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-4481	100.00	66.42	1669
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4745-5P	99.98	65.95	1028
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-2110	99.96	66.68	1930
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6892-3P	99.68	66.40	1178
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-4663	99.62	65.33	957
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-330-3P	99.41	69.95	2521

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 12.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 34)

• This study have identified, cloned and characterized PIKE-L, which localizes to both the cytoplasm and the nucleus, activates mGlur1 enhances formation of an mGluRI-Homer-PIKE-L complex, then activates PI3 kinase activity and prevents neuronal apoptosis. (PMID:14528310)
• a physiologic regulator of Akt and an oncogenic effector of cell invasion (PMID:14761976)
• PIKE binds PI 3-kinase & stimulates its lipid kinase activity. There are 3 isoforms which function throught the cell and meadiate processes from invasiveness to apoptosis. Review. (PMID:15951849)
• The AGAP2 colocalized with AP-1, transferrin receptor and Rab4 on endosomes. Overexpression of AGAP2 changed the intracellular distribution of AP-1 and promoted Rab4-dependent fast recycling of transferrin. (PMID:16079295)
• an important role of PIKE gene aberrations in the molecular pathogenesis of primary glioblastomas (PMID:16150119)
• Fyn is essential for phosphorylating PIKE-A and protects it from apoptotic cleavage. (PMID:16841086)
• The results of this study indicate that centaurins could be more accurately classified as NTPases and point to alternative mechanisms of cell signalling control. (PMID:17037982)
• Myxoma virus (MV) M-T5 host range protein is functionally interchangeable with the host PIKE-A protein and that the activation of host Akt by either M-T5 or PIKE-A is critical for the permissiveness of cancer cells for MV. (PMID:17151107)
• PIKE-A acts as a proto-oncogene, promoting cell transformation through Akt activation. (PMID:17297440)
• Ectopic expression of AGAP2 causes both BRAG2 and the coiled bodies’ marker coilin to accumulate in nucleoli. (PMID:17461797)
• The cytoplasmic-nuclear shuttling of PIKE is dynamically regulated by the balancing actions of the lipid-binding property of both the split PH domain and the nuclear targeting function of its nuclear localization sequence. (PMID:18371979)
• In normal mice. PIKE-L strongly binds SET and prevents its degradation by AEP, leading to resistance of neuronal cell death. (PMID:18374643)
• PIKE-L acts as a downstream survival effector for netrin-1 through UNC5B in the nervous system (PMID:18469807)
• Cdk5 phosphorylates PIKE-A and stimulates its GTPase activity, which activates nuclear Akt and promotes glioblastoma cell migration and invasion. (PMID:18487454)
• Increased GGAP2 expression, which is present in three quarters of human prostate cancers, can activate two critical pathways that have been linked to prostate cancer initiation and progression. (PMID:19176382)
• AGAP2 regulates the FAK activity and the focal adhesion disassembly during cell migration. (PMID:19318351)
• regulates retrograde protein transport between early endosomes and the Golgi complex (PMID:20551179)
• Akt-phosphorylated PIKE-A inhibits UNC5B-induced apoptosis in cancer cell lines in a p53-dependent manner. [PIKE-A] (PMID:21460185)
• PIKE is a critical factor in controlling synaptic AMPA receptor insertion. (PMID:21847098)
• PIKE is highly expressed in human squamous cell carcinoma and has a critical role in EGF-induced squamous cell carcinoma proliferation. (PMID:22349826)
• The presence of heterogeneous missense mutations of GGAP2 in prostate cancer was associated with aggressive clinical behavior. (PMID:22389719)
• Fyn regulates the activity of the adipogenic transcription factor signal transducer and activator of transcription 5a (STAT5a) through enhancing its interaction with the GTPase phosphoinositide 3-kinase enhancer A (PIKE-A). (PMID:23438599)
• AGAP2 plays a role in the signalling and recycling of beta2-adrenergic receptors. (PMID:23527545)
• In this review the CENTG1 gene is amplified in a variety of human cancers which lead to the enhancement of tumor invasion. (PMID:23770988)
• PIKE reduction rescued PI3K-dependent and -independent neuronal defects in fragile X syndrome. (PMID:25921541)
• Mutation of Fyn phosphorylation sites on PIKE-A, depletion of Fyn, or pharmacological inhibition of Fyn blunts the association between PIKE-A and AMPK, resulting in loss of its inhibitory effect on AMPK. (PMID:26001218)
• expression of PLC-gamma1 and PIKE positively correlated with the tumor differentiation of oral squamous cell carcinoma. (PMID:26464646)
• Studies showed that overexpression or mutation of PIKE has been observed in a variety of tumors, promoting cancer cell growth, transformation and invasion through AKT signaling or other signaling pathways, such as focal adhesion kinase. [review] (PMID:26977005)
• A pleckstrin homology domain in PIKE-L directly binds alpha-synuclein and antagonizes its aggregation. Accordingly, PIKE-L overexpression decreases dopaminergic cell death elicited by MPP(+), whereas PIKE-L knockdown elevates alpha-synuclein oligomerization and cell death. (PMID:28096359)
• these findings support that PIKE amplification or overexpression coordinately acts with CDK4 to drive glioblastoma tumorigenesis. (PMID:28368413)
• The role of AGAP2 in the pro-fibrogenic phenotype of hepatic stellate cells in response to TGFbeta. (PMID:30660615)
• chromatin immunoprecipitation studies revealed the presence of RARalpha, RXRalpha and the lysine acetyl transferase PCAF in AGAP2 promoter. (PMID:30674964)
• Exosomes derived from microRNA-199a-overexpressing mesenchymal stem cells inhibit glioma progression by down-regulating AGAP2. (PMID:31386624)
• PIKE-A promotes glioblastoma growth by driving PPP flux through increasing G6PD expression mediated by phosphorylation of STAT3. (PMID:34411567)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	agap2	ENSDARG00000099874
mus_musculus	Agap2	ENSMUSG00000025422
rattus_norvegicus	Agap2	ENSRNOG00000025584

Paralogs (28): ARAP2 (ENSG00000047365), ACAP1 (ENSG00000072818), SMAP2 (ENSG00000084070), ASAP3 (ENSG00000088280), ARFGAP1 (ENSG00000101199), ADAP1 (ENSG00000105963), AGFG2 (ENSG00000106351), GIT1 (ENSG00000108262), SMAP1 (ENSG00000112305), ACAP2 (ENSG00000114331), ARAP3 (ENSG00000120318), ACAP3 (ENSG00000131584), AGAP3 (ENSG00000133612), APPL2 (ENSG00000136044), GIT2 (ENSG00000139436), ARFGAP2 (ENSG00000149182), ASAP2 (ENSG00000151693), ASAP1 (ENSG00000153317), APPL1 (ENSG00000157500), AGAP1 (ENSG00000157985), AGAP5 (ENSG00000172650), AGFG1 (ENSG00000173744), ADAP2 (ENSG00000184060), ARAP1 (ENSG00000186635), AGAP4 (ENSG00000188234), AGAP6 (ENSG00000204149), AGAP9 (ENSG00000204172), ARFGAP3 (ENSG00000242247)

Protein

Protein identifiers

Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 2 — Q99490 (reviewed: Q99490)

Alternative names: Centaurin-gamma-1, GTP-binding and GTPase-activating protein 2, Phosphatidylinositol 3-kinase enhancer

All UniProt accessions (4): Q99490, F8VVT9, H0YHB1, J3KNM6

UniProt curated annotations — full annotation on UniProt →

Function. GTPase-activating protein (GAP) for ARF1 and ARF5, which also shows strong GTPase activity. Isoform 1 participates in the prevention of neuronal apoptosis by enhancing PI3 kinase activity. It aids the coupling of metabotropic glutamate receptor 1 (GRM1) to cytoplasmic PI3 kinase by interacting with Homer scaffolding proteins, and also seems to mediate anti-apoptotic effects of NGF by activating nuclear PI3 kinase. Isoform 2 does not stimulate PI3 kinase but may protect cells from apoptosis by stimulating Akt. It also regulates the adapter protein 1 (AP-1)-dependent trafficking of proteins in the endosomal system. It seems to be oncogenic. It is overexpressed in cancer cells, prevents apoptosis and promotes cancer cell invasion.

Subunit / interactions. Isoform 1 interacts with EPB41L1, PLCG1, NF2, HOMER1 and HOMER2. Isoform 2 interacts with activated AKT1 in the presence of guanine nucleotides, and with the AP-1 complex.

Subcellular location. Cytoplasm. Nucleus Cytoplasm.

Tissue specificity. Isoform 1 is brain-specific. Isoform 2 is ubiquitously expressed, with highest levels in brain and heart.

Post-translational modifications. Isoform PIKE-A is phosphorylated at Tyr-682 and Tyr-774 by FYN, preventing its apoptotic cleavage.

Activity regulation. GAP activity is stimulated by phosphatidylinositol 4,5-bisphosphate (PIP2) and, to a lesser extent, by phosphatidylinositol 3,4,5-trisphosphate (PIP3). Phosphatidic acid potentiates PIP2 stimulation.

Domain organisation. G domain binds GTP and has GTPase activity. Arf-GAP domain interacts with G domain and may regulate its GTPase activity. Although both PH domains of isoforms 1 and 2 bind phospholipids, they differently regulate subcellular location. PH domain of isoform 1 directs the protein to the nucleus, but PH domain of isoform 2 directs it to the cytosol. PH domain of isoform 2 is required for binding to AP-1.

Similarity. Belongs to the centaurin gamma-like family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q99490-1	1, PIKE-L	yes
Q99490-2	2, PIKE-A

RefSeq proteins (2): NP_001116244, NP_055585 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001164	ArfGAP_dom	Domain
IPR001806	Small_GTPase	Family
IPR001849	PH_domain	Domain
IPR002110	Ankyrin_rpt	Repeat
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR037278	ARFGAP/RecO	Homologous_superfamily
IPR038508	ArfGAP_dom_sf	Homologous_superfamily
IPR051282	Arf-GAP_GTPase_ANK_PH	Family

Pfam: PF00071, PF01412, PF12796

UniProt features (99 total): compositionally biased region 16, strand 16, modified residue 12, sequence variant 12, sequence conflict 11, region of interest 9, helix 8, domain 3, binding site 3, splice variant 3, repeat 2, turn 2, chain 1, zinc finger region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
2IWR	X-RAY DIFFRACTION	1.5
2BMJ	X-RAY DIFFRACTION	2.1
2RLO	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99490-F1	60.04	0.30

Functional residue map

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

Ligand- & substrate-binding residues (3): 413–420; 457–461; 515–518

Post-translational modifications (12): 113, 128, 149, 638, 750, 752, 808, 927, 985, 1178, 682, 774

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-373752	Netrin-1 signaling
R-HSA-1266738	Developmental Biology
R-HSA-422475	Axon guidance
R-HSA-9675108	Nervous system development

MSigDB gene sets: 164 (showing top): FXR_IR1_Q6, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, BENPORATH_ES_WITH_H3K27ME3, GOBP_REGULATION_OF_PHOSPHORYLATION, MODULE_255, PID_NETRIN_PATHWAY, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MODULE_317, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, TGACCTY_ERR1_Q2, GOBP_VESICLE_MEDIATED_TRANSPORT, CAGCTG_AP4_Q5, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOMF_KINASE_ACTIVATOR_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY

GO Biological Process (7): protein transport (GO:0015031), endosomal transport (GO:0016197), actin cytoskeleton organization (GO:0030036), negative regulation of protein catabolic process (GO:0042177), negative regulation of neuron apoptotic process (GO:0043524), positive regulation of protein kinase activity (GO:0045860), negative regulation of apoptotic process (GO:0043066)

GO Molecular Function (12): GTPase activity (GO:0003924), GTPase activator activity (GO:0005096), ATP binding (GO:0005524), GTP binding (GO:0005525), zinc ion binding (GO:0008270), protein kinase binding (GO:0019901), protein kinase activator activity (GO:0030295), phosphatidylinositol 3-kinase regulator activity (GO:0035014), phosphatidylinositol 3-kinase activator activity (GO:0141038), nucleotide binding (GO:0000166), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (8): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), endosome (GO:0005768), cytosol (GO:0005829), membrane (GO:0016020), extracellular exosome (GO:0070062), Flemming body (GO:0090543)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Axon guidance	1
Nervous system development	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
protein kinase activity	2
purine ribonucleoside triphosphate binding	2
transport	1
intracellular protein localization	1
establishment of protein localization	1
vesicle-mediated transport	1
intracellular transport	1
cytoskeleton organization	1
actin filament-based process	1
negative regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
negative regulation of protein metabolic process	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
positive regulation of protein phosphorylation	1
positive regulation of kinase activity	1
regulation of protein kinase activity	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
ribonucleoside triphosphate phosphatase activity	1
GTPase activity	1
enzyme activator activity	1
GTPase regulator activity	1
adenyl ribonucleotide binding	1
guanyl ribonucleotide binding	1
transition metal ion binding	1
kinase binding	1
kinase activator activity	1
protein kinase regulator activity	1
kinase regulator activity	1
phosphatidylinositol 3-kinase catalytic subunit binding	1
phosphatidylinositol 3-kinase regulator activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
cation binding	1

Protein interactions and networks

STRING

928 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AGAP2	LGMN	Q99538	729
AGAP2	EPB41L1	Q9H4G0	715
AGAP2	ANK1	P16157	631
AGAP2	ANK2	Q01484	622
AGAP2	ANK3	Q12955	619
AGAP2	SET	Q01105	588
AGAP2	PLEK2	Q9NYT0	549
AGAP2	ANP32A	P39687	549
AGAP2	SETBP1	Q9Y6X0	548
AGAP2	PLEK	P08567	546
AGAP2	NME1	P15531	492
AGAP2	DLGAP1	P78335	485
AGAP2	PPP1R9B	Q96SB3	472
AGAP2	GZMA	P12544	469
AGAP2	GRIA2	P42262	468

IntAct

15 interactions, top by confidence:

A	B	Type	Score
EPB41L1	AP3B1	psi-mi:“MI:0914”(association)	0.530
AGAP2	INSR	psi-mi:“MI:0915”(physical association)	0.520
INSR	AGAP2	psi-mi:“MI:0915”(physical association)	0.520
AGAP2	KRT17	psi-mi:“MI:0915”(physical association)	0.400
M-RIP	AGAP2	psi-mi:“MI:0915”(physical association)	0.400
Mprip	AGAP2	psi-mi:“MI:0915”(physical association)	0.370
Nr4a1	AGAP2	psi-mi:“MI:0915”(physical association)	0.370
Siah1a	AGAP2	psi-mi:“MI:0915”(physical association)	0.370
MCC	PER1	psi-mi:“MI:0914”(association)	0.350
SMAD4	AGAP2	psi-mi:“MI:2364”(proximity)	0.270
BTG3	AGAP2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (46): GRIP1 (Two-hybrid), AGAP2 (Two-hybrid), GRIP1 (Affinity Capture-Western), AGAP2 (Affinity Capture-Western), GRIP1 (Reconstituted Complex), GRIA2 (Affinity Capture-Western), AGAP2 (Affinity Capture-Western), CDC42 (Two-hybrid), RAC1 (Two-hybrid), RAC2 (Two-hybrid), RHOA (Two-hybrid), Rac1 (Two-hybrid), RHOA (Affinity Capture-Western), AGAP2 (Affinity Capture-Western), ARF1 (Biochemical Activity)

ESM2 similar proteins: A2XAV5, A2XED8, A2XVI8, A2XX39, A2Y3I2, A2Y5N0, A2YG32, A4GRC6, A8INQ0, B8AH02, B8AIK3, F5A894, F5HF68, O82268, P14348, P17473, P24939, P24940, P28925, Q0DZF3, Q0E3M2, Q0JAI1, Q3UHD9, Q5QD03, Q5W659, Q652I1, Q69T21, Q6ATW6, Q6K5X1, Q6NNI3, Q6S6U0, Q6Z869, Q71FD5, Q7XDD0, Q7XRS1, Q8CGU4, Q8GVZ6, Q8K3A9, Q8NHG8, Q941W1

Diamond homologs: A1L520, A1Z7A6, A5PK26, A6NIR3, O43150, O74345, O75689, O80925, O82171, O94601, O97902, P35197, P38682, P40529, P52594, Q04412, Q09531, Q0WQQ1, Q10165, Q10367, Q14161, Q15027, Q15057, Q17R07, Q1AAU6, Q1ZXH8, Q28CM8, Q2TA45, Q3MID3, Q3UHD9, Q4KLH5, Q4KLN7, Q4LDD4, Q4R4C9, Q5F413, Q5FVC7, Q5R787, Q5RAT7, Q5U464, Q5VTM2

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
FYN	up-regulates	AGAP2	phosphorylation
CDK5	up-regulates	AGAP2	phosphorylation
AKT1	up-regulates	AGAP2	phosphorylation
AKT	up-regulates	AGAP2	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	2
Uncertain significance	141
Likely benign	15
Benign	3

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
59019	GRCh38/hg38 12q13.3-14.2(chr12:57013355-63042498)x1	Pathogenic
59020	GRCh38/hg38 12q13.3-14.1(chr12:57041158-60273934)x1	Pathogenic
815528	GRCh37/hg19 12q13.2-14.1(chr12:55552371-62126304)x3	Pathogenic
1808720	GRCh37/hg19 12q13.3-14.1(chr12:57631073-58236597)x1	Likely pathogenic
815529	GRCh37/hg19 12q13.3-14.1(chr12:57582163-59031979)x1	Likely pathogenic

SpliceAI

2686 predictions. Top by Δscore:

Variant	Effect	Δscore
12:57726791:CGTA:C	acceptor_gain	1.0000
12:57726795:C:CC	acceptor_gain	1.0000
12:57726970:GTAC:G	donor_loss	1.0000
12:57726971:TAC:T	donor_loss	1.0000
12:57726972:A:AC	donor_gain	1.0000
12:57726972:AC:A	donor_gain	1.0000
12:57726973:C:CC	donor_gain	1.0000
12:57726973:CC:C	donor_gain	1.0000
12:57726973:CCCA:C	donor_gain	1.0000
12:57727225:CCTCC:C	acceptor_gain	1.0000
12:57727226:CTCC:C	acceptor_gain	1.0000
12:57727226:CTCCC:C	acceptor_gain	1.0000
12:57727227:TCC:T	acceptor_gain	1.0000
12:57727227:TCCCT:T	acceptor_gain	1.0000
12:57727228:CC:C	acceptor_gain	1.0000
12:57727228:CCC:C	acceptor_gain	1.0000
12:57727229:CC:C	acceptor_gain	1.0000
12:57727230:C:CC	acceptor_gain	1.0000
12:57727239:C:CT	acceptor_gain	1.0000
12:57727239:C:T	acceptor_gain	1.0000
12:57727240:A:T	acceptor_gain	1.0000
12:57727355:CTTA:C	donor_loss	1.0000
12:57727356:TTA:T	donor_loss	1.0000
12:57727357:TA:T	donor_loss	1.0000
12:57727358:A:AC	donor_gain	1.0000
12:57727358:A:AT	donor_loss	1.0000
12:57727358:AC:A	donor_gain	1.0000
12:57727359:C:CT	donor_gain	1.0000
12:57727359:CC:C	donor_gain	1.0000
12:57727359:CCG:C	donor_gain	1.0000

AlphaMissense

7601 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000167566 (12:57738162 G>A), RS1000198141 (12:57738532 T>C,G), RS1000358365 (12:57741050 G>C), RS1000543540 (12:57739883 G>A,C), RS1000717778 (12:57733928 T>C), RS1000792496 (12:57732245 G>A), RS1000812250 (12:57726177 T>A,C), RS1000899716 (12:57735621 T>G), RS1000972179 (12:57742297 A>C), RS1001087943 (12:57733497 G>T), RS1001238887 (12:57726463 G>A,C), RS1001248577 (12:57734951 T>C,G), RS1001386481 (12:57738916 G>T), RS1001547154 (12:57732672 G>A), RS1002065141 (12:57739007 C>A,G)

Disease associations

OMIM: gene MIM:605476 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): familial melanoma (MONDO:0018961)

Orphanet (1): Familial melanoma (Orphanet:618)

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001198_1	Multiple sclerosis	2.000000e-09
GCST006979_1062	Heel bone mineral density	4.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2069502	AGAP2, CDK4, MARCHF9, TSPAN31	3	2.00	1	somatropin recombinant

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects expression, increases abundance, increases expression	2
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
bisphenol A	affects cotreatment, increases methylation	1
ethyl-p-hydroxybenzoate	decreases expression	1
mono-(2-ethylhexyl)phthalate	increases abundance, decreases methylation	1
butyraldehyde	increases expression	1
pentanal	increases expression	1
CGP 52608	increases reaction, affects binding	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Aldehydes	increases expression	1
Arsenic	affects methylation	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Caffeine	affects phosphorylation	1
Diethylhexyl Phthalate	decreases methylation, increases abundance	1
Lead	affects expression	1
Ozone	affects expression, increases abundance	1
Rifampin	decreases expression	1
Smoke	decreases expression	1
Tretinoin	increases expression	1
Aflatoxin B1	increases methylation	1
Sodium Selenite	increases expression	1
Acrylamide	decreases expression	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06767332	Not specified	RECRUITING	EMDR for Fear of Cancer Recurrence in Patients with Familial Melanoma: a Waiting List Control Trial