AP2A2

Summary

AP2A2 (adaptor related protein complex 2 subunit alpha 2, HGNC:562) is a protein-coding gene on chromosome 11p15.5, encoding AP-2 complex subunit alpha-2 (O94973). Component of the adaptor protein complex 2 (AP-2).

The protein encoded by this gene is a subunit of the AP-2 adaptor protein complex, which is involved in linking lipid and protein membrane components with the clathrin lattice. This interaction supports the formation of clathrin-coated vesicles, and the encoded subunit aids in the process by binding polyphosphoinositide-containing lipids in the cell membrane.

Source: NCBI Gene 161 — RefSeq curated summary.

At a glance

• Gene–disease (curated): schizophrenia (Limited, GenCC)
• GWAS associations: 7
• Clinical variants (ClinVar): 142 total — 2 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_012305

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:562
Approved symbol	AP2A2
Name	adaptor related protein complex 2 subunit alpha 2
Location	11p15.5
Locus type	gene with protein product
Status	Approved
Aliases	DKFZP564D1864, HYPJ, KIAA0899, HIP9
Ensembl gene	ENSG00000183020
Ensembl biotype	protein_coding
OMIM	607242
Entrez	161

Gene structure

Transcript identifiers

Ensembl transcripts: 43 — 19 protein_coding, 14 retained_intron, 6 nonsense_mediated_decay, 4 protein_coding_CDS_not_defined

ENST00000332231, ENST00000448903, ENST00000524559, ENST00000524952, ENST00000525796, ENST00000525891, ENST00000526376, ENST00000526401, ENST00000526753, ENST00000527024, ENST00000527917, ENST00000528195, ENST00000528815, ENST00000528816, ENST00000529427, ENST00000529438, ENST00000529818, ENST00000529858, ENST00000530801, ENST00000531497, ENST00000531548, ENST00000534328, ENST00000534485, ENST00000685443, ENST00000686734, ENST00000687570, ENST00000687792, ENST00000687890, ENST00000688472, ENST00000688709, ENST00000688963, ENST00000689771, ENST00000689772, ENST00000690846, ENST00000691652, ENST00000693238, ENST00000860665, ENST00000860666, ENST00000860667, ENST00000860668, ENST00000860669, ENST00000916663, ENST00000947238

RefSeq mRNA: 2 — MANE Select: NM_012305 NM_001242837, NM_012305

CCDS: CCDS44512, CCDS73234

Canonical transcript exons

ENST00000448903 — 22 exons

Exon	Start	End
ENSE00001299193	993754	993985
ENSE00001323541	981198	981299
ENSE00001325685	988552	988689
ENSE00001593078	993284	993381
ENSE00001598094	984645	984753
ENSE00001665572	992503	992685
ENSE00001672910	985435	985582
ENSE00002160764	925870	926088
ENSE00002198155	1010548	1012240
ENSE00003466093	1009683	1009817
ENSE00003471082	986785	986953
ENSE00003474929	1006528	1006617
ENSE00003487309	1009328	1009397
ENSE00003496098	977095	977224
ENSE00003508496	1003722	1003804
ENSE00003524999	1008012	1008135
ENSE00003548307	1000432	1000598
ENSE00003614797	994072	994245
ENSE00003634002	959437	959505
ENSE00003668897	1009100	1009216
ENSE00003669428	970169	970311
ENSE00003691596	972062	972255

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 98.53.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 62.7012 / max 489.8233, expressed in 1823 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
112333	62.0786	1823
112334	0.3273	123
112335	0.1208	37
112339	0.0716	21
112337	0.0672	37
112336	0.0303	7
112332	0.0028	2
112331	0.0026	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	98.53	gold quality
cerebellum	UBERON:0002037	98.41	gold quality
cerebellar cortex	UBERON:0002129	98.40	gold quality
cerebellar hemisphere	UBERON:0002245	98.40	gold quality
spleen	UBERON:0002106	98.13	gold quality
superior frontal gyrus	UBERON:0002661	97.53	gold quality
sural nerve	UBERON:0015488	97.12	gold quality
cortical plate	UBERON:0005343	96.63	gold quality
right frontal lobe	UBERON:0002810	96.52	gold quality
metanephros cortex	UBERON:0010533	96.38	gold quality
tibial nerve	UBERON:0001323	96.27	gold quality
frontal cortex	UBERON:0001870	96.27	gold quality
subcutaneous adipose tissue	UBERON:0002190	96.24	gold quality
cortex of kidney	UBERON:0001225	96.08	gold quality
prefrontal cortex	UBERON:0000451	96.06	gold quality
endocervix	UBERON:0000458	96.04	gold quality
adipose tissue	UBERON:0001013	95.98	gold quality
pituitary gland	UBERON:0000007	95.92	gold quality
ganglionic eminence	UBERON:0004023	95.75	gold quality
body of uterus	UBERON:0009853	95.75	gold quality
upper lobe of left lung	UBERON:0008952	95.73	gold quality
omental fat pad	UBERON:0010414	95.72	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.70	gold quality
kidney	UBERON:0002113	95.65	gold quality
adult mammalian kidney	UBERON:0000082	95.64	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	95.60	gold quality
right lung	UBERON:0002167	95.59	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.59	gold quality
right ovary	UBERON:0002118	95.58	gold quality
lower esophagus	UBERON:0013473	95.56	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	14.66

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

30 targeting AP2A2, 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-4455	100.00	65.48	1587
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-623	99.76	68.16	1170
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-1287-3P	99.63	66.93	492
HSA-MIR-17-3P	99.55	66.77	1311
HSA-MIR-6832-3P	99.52	70.44	1726
HSA-MIR-4735-5P	99.43	68.49	1780
HSA-MIR-4777-5P	99.33	67.53	1148
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-1286	99.09	66.23	1046
HSA-MIR-4722-5P	98.46	66.34	1611
HSA-MIR-6780A-3P	98.42	67.49	1518
HSA-MIR-6742-3P	97.95	64.50	1490
HSA-MIR-6747-3P	97.73	64.84	1596
HSA-MIR-6787-5P	97.54	63.85	457
HSA-MIR-3674	97.01	68.86	1171
HSA-MIR-663A	94.99	63.54	378
HSA-MIR-10396B-5P	94.99	63.57	358
HSA-MIR-1908-5P	94.99	63.41	352

Literature-anchored findings (GeneRIF, showing 8)

• the AP-2 complex is not associated with the endocytosed plasma membrane-associated clathrin (PMID:14530274)
• The mutation of lysine-297 and arginine-340 on the alpha-adaptin specifically inhibits the ability of Nef to bind AP-2 and downregulate CD4. (PMID:19129443)
• Clathrin-dependent endocytosis of human CD317 from the cell surface lipid rafts is mediated by direct interaction with alpha-adaptin. (PMID:19359243)
• A protein encoded by this locus was found to be differentially expressed in postmortem brains from patients with atypical frontotemporal lobar degeneration. (PMID:22360420)
• AP2 has evolved as a key regulatory node to coordinate clarhtin-coated pit formation and cargo sorting and ensure high spatial and temporal regulation of cathrin-mediated endocytosis. (PMID:28003333)
• T allele and TT genotype in rs7396366, closest to the AP2A2 gene, are linked to an increased risk of coronary artery disease and its severity in a Chinese population. (PMID:30086706)
• We found evidence of late-onset Alzheimer disease-associated genetic polymorphism within an exon of Mucin 6 (MUC6) and immediately downstream from another gene: AP2A2 (PMID:31748784)
• AP2A2 mutation and defective endocytosis in a Malian family with hereditary spastic paraplegia. (PMID:38772452)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ap2a2	ENSMUSG00000002957
rattus_norvegicus	Ap2a2	ENSRNOG00000019534
drosophila_melanogaster	AP-2alpha	FBGN0264855
caenorhabditis_elegans		WBGENE00000161

Paralogs (4): AP4E1 (ENSG00000081014), AP1G1 (ENSG00000166747), AP2A1 (ENSG00000196961), AP1G2 (ENSG00000213983)

Protein

Protein identifiers

AP-2 complex subunit alpha-2 — O94973 (reviewed: O94973)

Alternative names: 100 kDa coated vesicle protein C, Adaptor protein complex AP-2 subunit alpha-2, Adaptor-related protein complex 2 subunit alpha-2, Alpha-adaptin C, Alpha2-adaptin, Clathrin assembly protein complex 2 alpha-C large chain, Huntingtin yeast partner J, Huntingtin-interacting protein 9, Huntingtin-interacting protein J, Plasma membrane adaptor HA2/AP2 adaptin alpha C subunit

All UniProt accessions (8): A0A8I5KPP9, A0A8I5KV06, A0A8I5KY83, A0A8I5KYZ9, A0A8I5QJV7, E9PPY8, E9PQP4, O94973

UniProt curated annotations — full annotation on UniProt →

Function. Component of the adaptor protein complex 2 (AP-2). Adaptor protein complexes function in protein transport via transport vesicles in different membrane traffic pathways. Adaptor protein complexes are vesicle coat components and appear to be involved in cargo selection and vesicle formation. AP-2 is involved in clathrin-dependent endocytosis in which cargo proteins are incorporated into vesicles surrounded by clathrin (clathrin-coated vesicles, CCVs) which are destined for fusion with the early endosome. The clathrin lattice serves as a mechanical scaffold but is itself unable to bind directly to membrane components. Clathrin-associated adaptor protein (AP) complexes which can bind directly to both the clathrin lattice and to the lipid and protein components of membranes are considered to be the major clathrin adaptors contributing the CCV formation. AP-2 also serves as a cargo receptor to selectively sort the membrane proteins involved in receptor-mediated endocytosis. AP-2 seems to play a role in the recycling of synaptic vesicle membranes from the presynaptic surface. AP-2 recognizes Y-X-X-[FILMV] (Y-X-X-Phi) and [ED]-X-X-X-L-[LI] endocytosis signal motifs within the cytosolic tails of transmembrane cargo molecules. AP-2 may also play a role in maintaining normal post-endocytic trafficking through the ARF6-regulated, non-clathrin pathway. During long-term potentiation in hippocampal neurons, AP-2 is responsible for the endocytosis of ADAM10. The AP-2 alpha subunit binds polyphosphoinositide-containing lipids, positioning AP-2 on the membrane. The AP-2 alpha subunit acts via its C-terminal appendage domain as a scaffolding platform for endocytic accessory proteins. The AP-2 alpha and AP-2 sigma subunits are thought to contribute to the recognition of the [ED]-X-X-X-L-[LI] motif.

Subunit / interactions. Adaptor protein complex 2 (AP-2) is a heterotetramer composed of two large adaptins (alpha-type subunit AP2A1 or AP2A2 and beta-type subunit AP2B1), a medium adaptin (mu-type subunit AP2M1) and a small adaptin (sigma-type subunit AP2S1). Binds EPN1, EPS15, AMPH, SNAP91 and BIN1. Interacts with HIP1. Interacts with DGKD. Interacts with DENND1A, DENND1B and DENND1C. Interacts with FCHO1 and DAB2. Interacts with ATAT1; this interaction is required for efficient alpha-tubulin acetylation by ATAT1. Interacts with KIAA1107. Together with AP2B1 and AP2M1, it interacts with ADAM10; this interaction facilitates ADAM10 endocytosis from the plasma membrane during long-term potentiation in hippocampal neurons. Interacts with CLN3 (via dileucine motif). Interacts with ABCB11; this interaction regulates cell membrane expression of ABCB11 through its internalization in a clathrin-dependent manner and its subsequent degradation. Interacts with Cacfd1. Interacts with DNAJC6.

Subcellular location. Cell membrane. Membrane. Coated pit.

Tissue specificity. Expressed in the brain (at protein level).

Similarity. Belongs to the adaptor complexes large subunit family.

Isoforms (3)

UniProt ID	Names	Canonical?
O94973-1	1	yes
O94973-2	2
O94973-3	3

RefSeq proteins (2): NP_001229766, NP_036437* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002553	Clathrin/coatomer_adapt-like_N	Domain
IPR003164	Clathrin_a-adaptin_app_sub_C	Domain
IPR008152	Clathrin_a/b/g-adaptin_app_Ig	Domain
IPR009028	Coatomer/calthrin_app_sub_C	Homologous_superfamily
IPR011989	ARM-like	Homologous_superfamily
IPR012295	TBP_dom_sf	Homologous_superfamily
IPR013041	Clathrin_app_Ig-like_sf	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR017104	AP2_complex_asu	Family
IPR050840	Adaptor_Complx_Large_Subunit	Family

Pfam: PF01602, PF02296, PF02883

UniProt features (13 total): binding site 4, splice variant 3, sequence conflict 2, compositionally biased region 2, chain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O94973-F1	85.30	0.58

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 (4): 11–12; 43; 53; 57–61

Function

Pathways and Gene Ontology

Reactome pathways

44 pathways

ID	Pathway
R-HSA-167590	Nef Mediated CD4 Down-regulation
R-HSA-177504	Retrograde neurotrophin signalling
R-HSA-182218	Nef Mediated CD8 Down-regulation
R-HSA-2132295	MHC class II antigen presentation
R-HSA-3928665	EPH-ephrin mediated repulsion of cells
R-HSA-437239	Recycling pathway of L1
R-HSA-5099900	WNT5A-dependent internalization of FZD4
R-HSA-5140745	WNT5A-dependent internalization of FZD2, FZD5 and ROR2
R-HSA-6798695	Neutrophil degranulation
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-8866427	VLDLR internalisation and degradation
R-HSA-8964038	LDL clearance
R-HSA-9679191	Potential therapeutics for SARS
R-HSA-9918485	Dengue Virus Attachment and Entry
R-HSA-416993	Trafficking of GluR2-containing AMPA receptors
R-HSA-1266738	Developmental Biology
R-HSA-1280218	Adaptive Immune System
R-HSA-162582	Signal Transduction
R-HSA-162906	HIV Infection
R-HSA-162909	Host Interactions of HIV factors
R-HSA-1643685	Disease
R-HSA-164938	Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters
R-HSA-164952	The role of Nef in HIV-1 replication and disease pathogenesis
R-HSA-166520	Signaling by NTRKs
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-174824	Plasma lipoprotein assembly, remodeling, and clearance
R-HSA-187037	Signaling by NTRK1 (TRKA)
R-HSA-195721	Signaling by WNT

MSigDB gene sets: 278 (showing top): MORF_RAGE, REACTOME_RETROGRADE_NEUROTROPHIN_SIGNALLING, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, IVANOVA_HEMATOPOIESIS_MATURE_CELL, REACTOME_THE_ROLE_OF_NEF_IN_HIV_1_REPLICATION_AND_DISEASE_PATHOGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, GOBP_SYNAPTIC_VESICLE_RECYCLING, STARK_HYPPOCAMPUS_22Q11_DELETION_UP, REACTOME_NEF_MEDIATES_DOWN_MODULATION_OF_CELL_SURFACE_RECEPTORS_BY_RECRUITING_THEM_TO_CLATHRIN_ADAPTERS

GO Biological Process (7): intracellular protein transport (GO:0006886), vesicle-mediated transport (GO:0016192), synaptic vesicle endocytosis (GO:0048488), clathrin-dependent endocytosis (GO:0072583), postsynaptic neurotransmitter receptor internalization (GO:0098884), endocytosis (GO:0006897), protein transport (GO:0015031)

GO Molecular Function (7): lipid binding (GO:0008289), protein kinase binding (GO:0019901), clathrin-cargo adaptor activity (GO:0035615), disordered domain specific binding (GO:0097718), protein binding (GO:0005515), kinase binding (GO:0019900), protein domain specific binding (GO:0019904)

GO Cellular Component (22): cytosol (GO:0005829), plasma membrane (GO:0005886), cytoplasmic side of plasma membrane (GO:0009898), AP-2 adaptor complex (GO:0030122), endocytic vesicle membrane (GO:0030666), secretory granule membrane (GO:0030667), clathrin-coated endocytic vesicle membrane (GO:0030669), cytoplasmic vesicle (GO:0031410), endolysosome membrane (GO:0036020), clathrin-coated endocytic vesicle (GO:0045334), presynapse (GO:0098793), postsynapse (GO:0098794), ficolin-1-rich granule membrane (GO:0101003), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), clathrin-coated pit (GO:0005905), endomembrane system (GO:0012505), membrane (GO:0016020), membrane coat (GO:0030117), AP-1 adaptor complex (GO:0030121), clathrin adaptor complex (GO:0030131), intracellular vesicle (GO:0097708)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	2
PCP/CE pathway	2
Plasma lipoprotein clearance	2
Signaling by NTRK1 (TRKA)	1
Adaptive Immune System	1
EPH-Ephrin signaling	1
L1CAM interactions	1
Innate Immune System	1
Clathrin-mediated endocytosis	1
Membrane Trafficking	1
SARS-CoV Infections	1
Dengue Virus Infection	1
Trafficking of AMPA receptors	1
Immune System	1
Viral Infection Pathways	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
cytoplasm	4
intracellular protein localization	2
transport	2
binding	2
membrane	2
plasma membrane	2
clathrin adaptor complex	2
endocytic vesicle	2
cytoplasmic vesicle membrane	2
bounding membrane of organelle	2
synapse	2
endomembrane system	2
protein transport	1
intracellular transport	1
cellular process	1
synaptic vesicle recycling	1
presynaptic endocytosis	1
receptor-mediated endocytosis	1
regulation of postsynaptic membrane neurotransmitter receptor levels	1
neurotransmitter receptor internalization	1
postsynaptic endocytosis	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
establishment of protein localization	1
kinase binding	1
clathrin binding	1
cargo adaptor activity	1
protein domain specific binding	1
enzyme binding	1
protein binding	1
cell periphery	1
cytoplasmic side of membrane	1
clathrin coat of endocytic vesicle	1
clathrin coat of coated pit	1
plasma membrane protein complex	1
secretory granule	1
clathrin-coated vesicle membrane	1

Protein interactions and networks

STRING

2770 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AP2A2	AP2M1	P20172	948
AP2A2	AP2S1	P53680	865
AP2A2	AP2B1	P21851	835
AP2A2	HTT	P42858	793
AP2A2	SNAP91	O60641	624
AP2A2	PICALM	Q13492	520
AP2A2	AMPH	P49418	510
AP2A2	SHC1	P29353	483
AP2A2	BIN1	O00499	480
AP2A2	EPN1	Q9Y6I3	465
AP2A2	RAB14	P35287	462
AP2A2	EPS15	P42566	460
AP2A2	ZCRB1	Q8TBF4	456
AP2A2	RAB10	P61026	440
AP2A2	CLTC	Q00610	440

IntAct

152 interactions, top by confidence:

A	B	Type	Score
ANKRD28	PPP6C	psi-mi:“MI:0914”(association)	0.870
SNX9	SYNJ1	psi-mi:“MI:0914”(association)	0.790
EGFR	CTNND1	psi-mi:“MI:0914”(association)	0.750
AMPH	BIN1	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
AP2A2	AAGAB	psi-mi:“MI:0915”(physical association)	0.670
AAGAB	AP2A2	psi-mi:“MI:0914”(association)	0.670
rep	AP2A2	psi-mi:“MI:0914”(association)	0.660
AP2A2	rep	psi-mi:“MI:0915”(physical association)	0.660
AP2S1	AP2A2	psi-mi:“MI:0914”(association)	0.640
GPR156	PLD2	psi-mi:“MI:0914”(association)	0.640
SNX9	WASL	psi-mi:“MI:0914”(association)	0.640
SHC1	AP2A2	psi-mi:“MI:0914”(association)	0.640
PRKCZ	IPO5	psi-mi:“MI:0914”(association)	0.530
EGFR	NDUFA4	psi-mi:“MI:0914”(association)	0.530
AP2B1	AP2A2	psi-mi:“MI:0914”(association)	0.530
CLTB	PIK3C2A	psi-mi:“MI:0914”(association)	0.530
EPS15	AP2A2	psi-mi:“MI:0914”(association)	0.530
NECAP2	AP2A2	psi-mi:“MI:0914”(association)	0.530
GPBP1L1	CNOT1	psi-mi:“MI:0914”(association)	0.530
AAGAB	STXBP3	psi-mi:“MI:0914”(association)	0.530
CLINT1	PIK3C2A	psi-mi:“MI:0914”(association)	0.530
EPS15L1	NDC80	psi-mi:“MI:0914”(association)	0.530

BioGRID (321): PIP5K1C (Affinity Capture-Western), ATP1A1 (Affinity Capture-Western), AP2A2 (Affinity Capture-RNA), AP2A2 (Affinity Capture-RNA), AP2A2 (Affinity Capture-MS), AP2A2 (Affinity Capture-MS), AP2A2 (Affinity Capture-MS), AP2A2 (Affinity Capture-MS), AP2A2 (Affinity Capture-MS), AP2A2 (Affinity Capture-MS), AP2A2 (Affinity Capture-MS), AP1B1 (Co-fractionation), AP2A2 (Co-fractionation), AP2A2 (Co-fractionation), AP2A2 (Co-fractionation)

ESM2 similar proteins: A0A8I3PI99, A0M8U1, A7Y521, B5DEN9, C5HGF3, O88544, O94973, P13666, P17427, P18484, P38024, Q00765, Q0VCK5, Q0X0A5, Q13098, Q1RLU8, Q28635, Q2PG42, Q3KNM2, Q3SZA0, Q3T0N3, Q3T126, Q3T178, Q3ZC24, Q4R5E6, Q5F418, Q5I0H4, Q5M7T4, Q5R648, Q5R9B0, Q5R9M4, Q5RE33, Q5ZJ41, Q5ZJD7, Q6DGW9, Q6GM44, Q6NRT5, Q7TQ48, Q8C407, Q8R1Z9

Diamond homologs: A0A0G2JV04, O43747, O75843, O88512, O94973, O95782, P17426, P17427, P18484, P22892, Q0VCK5, Q12028, Q5R5M2, Q6P5E6, Q84K16, Q8BMI3, Q8I8U2, Q99128, Q9NZ52, Q9UJY4, Q9UU81, Q9ZUI6, Q8R0H9, Q9UJY5, P91926, Q29N38, Q7QG73, Q86KI1, Q8LPK4, Q8LPL6, Q9C0W7

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
AP2A2	“form complex”	“AP-2 complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 158 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
WNT5A-dependent internalization of FZD4	6	42.7×	3e-07
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	5	29.6×	3e-05
The role of Nef in HIV-1 replication and disease pathogenesis	5	29.6×	3e-05
LDL clearance	5	25.4×	6e-05
Clathrin-mediated endocytosis	28	22.3×	6e-28
Golgi Associated Vesicle Biogenesis	10	18.7×	1e-08
Cargo recognition for clathrin-mediated endocytosis	18	17.6×	2e-15
Host Interactions of HIV factors	5	15.7×	5e-04

GO biological processes:

GO term	Partners	Fold	FDR
clathrin coat assembly	10	66.7×	6e-14
synaptic vesicle endocytosis	11	35.7×	4e-12
clathrin-dependent endocytosis	8	35.0×	1e-08
endocytosis	15	10.7×	4e-09
regulation of protein localization	6	9.3×	6e-03
vesicle-mediated transport	9	6.5×	2e-03
intracellular protein transport	12	5.8×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	118
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
58855	GRCh38/hg38 11p15.5(chr11:758848-1998025)x1	Pathogenic
815395	GRCh37/hg19 11p15.5-13(chr11:235934-33826995)x3	Pathogenic

SpliceAI

5603 predictions. Top by Δscore:

Variant	Effect	Δscore
11:1000430:A:AG	acceptor_gain	1.0000
11:1000431:G:GG	acceptor_gain	1.0000
11:1008133:CAGG:C	donor_loss	1.0000
11:1008134:AGG:A	donor_loss	1.0000
11:1008136:GTAAG:G	donor_loss	1.0000
11:1009085:T:A	acceptor_gain	1.0000
11:1009088:T:A	acceptor_gain	1.0000
11:1009096:GCAGG:G	acceptor_loss	1.0000
11:1009097:CAGGT:C	acceptor_loss	1.0000
11:1009098:A:T	acceptor_loss	1.0000
11:1009209:T:G	donor_gain	1.0000
11:1009213:GCAA:G	donor_gain	1.0000
11:1009215:AAGT:A	donor_loss	1.0000
11:1009216:AGTG:A	donor_loss	1.0000
11:1009217:G:GG	donor_gain	1.0000
11:1009217:GT:G	donor_loss	1.0000
11:1009316:T:A	acceptor_gain	1.0000
11:1009323:CACA:C	acceptor_loss	1.0000
11:1009324:A:AG	acceptor_gain	1.0000
11:1009325:C:G	acceptor_gain	1.0000
11:1009325:CAGT:C	acceptor_loss	1.0000
11:1009326:A:AG	acceptor_gain	1.0000
11:1009327:G:GA	acceptor_gain	1.0000
11:1009327:GT:G	acceptor_gain	1.0000
11:1009327:GTC:G	acceptor_gain	1.0000
11:1009327:GTCC:G	acceptor_gain	1.0000
11:1009327:GTCCA:G	acceptor_gain	1.0000
11:1009394:CAAGG:C	donor_loss	1.0000
11:1009395:AAGGT:A	donor_loss	1.0000
11:1009396:AGGTA:A	donor_loss	1.0000

AlphaMissense

6147 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:1006553:T:A	N744K	1.000
11:1006553:T:G	N744K	1.000
11:1009200:T:A	W841R	1.000
11:1009200:T:C	W841R	1.000
11:1009202:G:C	W841C	1.000
11:1009202:G:T	W841C	1.000
11:1009780:G:A	G902E	1.000
11:1009786:T:C	L904P	1.000
11:1009791:C:A	R906S	1.000
11:1009792:G:C	R906P	1.000
11:1010555:G:C	R917P	1.000
11:1010558:T:C	L918P	1.000
11:1010566:C:A	R921S	1.000
11:1010567:G:C	R921P	1.000
11:926055:G:C	G12R	1.000
11:926056:G:A	G12D	1.000
11:926059:T:A	L13Q	1.000
11:926059:T:C	L13P	1.000
11:926067:T:C	F16L	1.000
11:926068:T:C	F16S	1.000
11:926068:T:G	F16C	1.000
11:926069:C:A	F16L	1.000
11:926069:C:G	F16L	1.000
11:926071:T:A	I17N	1.000
11:926082:C:A	R21S	1.000
11:926083:G:C	R21P	1.000
11:959464:G:T	R32M	1.000
11:959465:G:C	R32S	1.000
11:959465:G:T	R32S	1.000
11:959467:T:A	I33K	1.000

dbSNP variants (sampled 300 via entrez): RS1000057640 (11:955760 T>C), RS1000057933 (11:965410 T>C), RS1000081595 (11:942188 A>G), RS1000087804 (11:988799 T>A,C,G), RS1000124621 (11:1004728 A>T), RS1000125892 (11:1010536 T>C), RS1000175048 (11:1002508 G>C), RS1000206072 (11:1002636 G>A,T), RS1000211513 (11:934708 T>G), RS1000236480 (11:927348 A>G), RS1000242623 (11:934936 G>A), RS1000256878 (11:932995 C>T), RS1000259298 (11:969978 T>G), RS1000280933 (11:979935 T>A), RS1000311488 (11:975142 G>C,T)

Disease associations

OMIM: gene MIM:607242 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
schizophrenia	Limited	Unknown

Mondo (2): breast ductal adenocarcinoma (MONDO:0005590), schizophrenia (MONDO:0005090)

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST002245_27	Alzheimer’s disease (late onset)	6.000000e-07
GCST002625_2	Chronic bronchitis and chronic obstructive pulmonary disease	5.000000e-08
GCST003833_3	Adult asthma	2.000000e-07
GCST006303_17	Nicotine withdrawal symptom count	7.000000e-08
GCST006869_9	Nicotine withdrawal	3.000000e-07
GCST007600_9	Alzheimer’s disease	4.000000e-06
GCST009798_52	Asthma	2.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009263	nicotine withdrawal symptom count
EFO:0009362	nicotine withdrawal measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066994 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, affects methylation, decreases expression	3
bisphenol A	increases expression, decreases methylation	2
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, affects expression	2
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Ozone	affects cotreatment, increases oxidation, increases abundance, affects expression	2
Smoke	decreases expression	2
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol S	decreases methylation	1
Sunitinib	increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Cisplatin	decreases expression	1
Dactinomycin	affects cotreatment, increases secretion	1
Diazinon	increases methylation	1
Ivermectin	decreases expression	1
Manganese	decreases expression, increases abundance, affects cotreatment	1
Mercury	decreases expression	1
Rotenone	increases expression	1
Selenium	increases expression	1
Dronabinol	increases expression	1
Valproic Acid	increases methylation	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5650906	Binding	Binding affinity to human AP2A2 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_AR69	HeLa-Mitotrap-Ap2a2-FKBP	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety