AP2A1

Summary

AP2A1 (adaptor related protein complex 2 subunit alpha 1, HGNC:561) is a protein-coding gene on chromosome 19q13.33, encoding AP-2 complex subunit alpha-1 (O95782). Component of the adaptor protein complex 2 (AP-2).

This gene encodes the alpha 1 adaptin subunit of the adaptor protein 2 (AP-2) complex found in clathrin coated vesicles. The AP-2 complex is a heterotetramer consisting of two large adaptins (alpha or beta), a medium adaptin (mu), and a small adaptin (sigma). The complex is part of the protein coat on the cytoplasmic face of coated vesicles which links clathrin to receptors in vesicles. Alternative splicing of this gene results in two transcript variants encoding two different isoforms. A third transcript variant has been described, but its full length nature has not been determined.

Source: NCBI Gene 160 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 140 total
• Druggable target: yes
• MANE Select transcript: NM_130787

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:561
Approved symbol	AP2A1
Name	adaptor related protein complex 2 subunit alpha 1
Location	19q13.33
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000196961
Ensembl biotype	protein_coding
OMIM	601026
Entrez	160

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 4 protein_coding, 4 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000354293, ENST00000359032, ENST00000593788, ENST00000594838, ENST00000597774, ENST00000600199, ENST00000600466, ENST00000601356, ENST00000938965, ENST00000955907

RefSeq mRNA: 2 — MANE Select: NM_130787 NM_014203, NM_130787

CCDS: CCDS46148, CCDS46149

Canonical transcript exons

ENST00000354293 — 23 exons

Exon	Start	End
ENSE00001260851	49767001	49767200
ENSE00001626943	49799968	49800150
ENSE00001789865	49800961	49801058
ENSE00002319301	49806681	49807114
ENSE00003467005	49801390	49801621
ENSE00003487325	49792991	49793092
ENSE00003499691	49795630	49795738
ENSE00003506877	49803107	49803189
ENSE00003523785	49781947	49782089
ENSE00003534226	49805872	49805941
ENSE00003542012	49805661	49805777
ENSE00003543409	49802949	49803005
ENSE00003547768	49798802	49798952
ENSE00003558762	49806119	49806253
ENSE00003585120	49801981	49802141
ENSE00003602101	49803287	49803376
ENSE00003609661	49791935	49792064
ENSE00003629055	49801722	49801889
ENSE00003644493	49799629	49799766
ENSE00003652682	49781757	49781825
ENSE00003668265	49805453	49805576
ENSE00003671083	49799327	49799495
ENSE00003686856	49782531	49782724

Expression profiles

Bgee: expression breadth ubiquitous, 243 present calls, max score 98.40.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 82.7529 / max 630.4585, expressed in 1821 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
177057	79.9396	1820
177058	1.1489	661
177066	0.8122	414
177065	0.5198	261
177067	0.2001	53
177056	0.1324	24

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland	UBERON:0001233	98.40	gold quality
right adrenal gland cortex	UBERON:0035827	98.38	gold quality
left adrenal gland	UBERON:0001234	98.26	gold quality
left adrenal gland cortex	UBERON:0035825	98.23	gold quality
left testis	UBERON:0004533	97.80	gold quality
adrenal cortex	UBERON:0001235	97.79	gold quality
right testis	UBERON:0004534	97.79	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.63	gold quality
right frontal lobe	UBERON:0002810	97.52	gold quality
cerebellar hemisphere	UBERON:0002245	97.22	gold quality
cerebellar cortex	UBERON:0002129	97.17	gold quality
adrenal gland	UBERON:0002369	96.93	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.89	gold quality
right ovary	UBERON:0002118	96.43	gold quality
cerebellum	UBERON:0002037	96.18	gold quality
stromal cell of endometrium	CL:0002255	96.14	gold quality
anterior cingulate cortex	UBERON:0009835	96.11	gold quality
left ovary	UBERON:0002119	96.01	gold quality
prefrontal cortex	UBERON:0000451	95.91	gold quality
lower esophagus mucosa	UBERON:0035834	95.86	gold quality
buccal mucosa cell	CL:0002336	95.83	gold quality
body of uterus	UBERON:0009853	95.78	gold quality
gastrocnemius	UBERON:0001388	95.74	gold quality
cortical plate	UBERON:0005343	95.71	gold quality
left uterine tube	UBERON:0001303	95.63	gold quality
apex of heart	UBERON:0002098	95.61	gold quality
granulocyte	CL:0000094	95.53	gold quality
ectocervix	UBERON:0012249	95.46	gold quality
mucosa of stomach	UBERON:0001199	95.37	gold quality
skin of leg	UBERON:0001511	95.35	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.50
E-MTAB-3929	no	152.85

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

38 targeting AP2A1, 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-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-7110-3P	100.00	73.18	2486
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4728-5P	99.85	69.39	4718
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-6756-5P	99.82	67.97	2466
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-6768-3P	99.14	67.38	1319
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-6737-3P	98.95	68.56	1577
HSA-MIR-7157-3P	98.95	68.70	1582
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-6889-3P	98.84	67.35	1198
HSA-MIR-331-3P	98.76	64.91	793
HSA-MIR-5008-3P	98.73	67.50	1433

Literature-anchored findings (GeneRIF, showing 6)

• AP2alpha negatively regulates HIV-1 replication in the process of nuclear translocation of viral DNA in the cytoplasm or the perinuclear region. (PMID:18178234)
• nef usurps AP-2 complexes to dysregulate Ii (invariant chain (Ii)/major histocompatibility complex class II) trafficking and potentially interfere with antigen presentation in the context of MHC-II (PMID:18524831)
• A protein encoded by this locus was found to be differentially expressed in postmortem brains from patients with atypical frontotemporal lobar degeneration. (PMID:22360420)
• These results lead to a model for the docking of the full AP-2 tetramer to membranes as bound to Nef, such that the cytosolic tail of CD4 is situated to interact with its binding site on Nef. (PMID:24473078)
• AP-2alpha depletion enhanced apoptosis, demonstrating that disrupting the HIV-1 Nef:AP-2alpha interaction limits Nef-mediated apoptosis. (PMID:28577469)
• Results revealed thirteen novel splice junctions of previously annotated exons. Consecutive nested PCRs led to the determination of the primary structure of seventy-seven novel AP2A1 transcripts, all of which were shown to comprise at least one premature translation termination codon, thus representing nonsense-mediated mRNA decay candidates. (PMID:30081190)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ap2a1	ENSDARG00000054320
mus_musculus	Ap2a1	ENSMUSG00000060279
rattus_norvegicus	Ap2a1	ENSRNOG00000026243
drosophila_melanogaster	AP-2alpha	FBGN0264855
caenorhabditis_elegans		WBGENE00000161

Paralogs (4): AP4E1 (ENSG00000081014), AP1G1 (ENSG00000166747), AP2A2 (ENSG00000183020), AP1G2 (ENSG00000213983)

Protein

Protein identifiers

AP-2 complex subunit alpha-1 — O95782 (reviewed: O95782)

Alternative names: 100 kDa coated vesicle protein A, Adaptor protein complex AP-2 subunit alpha-1, Adaptor-related protein complex 2 subunit alpha-1, Alpha-adaptin A, Alpha1-adaptin, Clathrin assembly protein complex 2 alpha-A large chain, Plasma membrane adaptor HA2/AP2 adaptin alpha A subunit

All UniProt accessions (2): O95782, M0R2D9

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). Interacts with SGIP1. Interacts with HIP1 and RAB11FIP2. Interacts with SLC12A5. Interacts with clathrin. Interacts with RFTN1. Interacts with KIAA1107. Interacts with PICALM. 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 ABCB11; this interaction regulates cell membrane expression of ABCB11 through its internalization in a clathrin-dependent manner and its subsequent degradation.

Subcellular location. Cell membrane. Membrane. Coated pit.

Tissue specificity. Expressed in the brain (at protein level). Isoform A: Expressed in forebrain, skeletal muscle, spinal cord, cerebellum, salivary gland, heart and colon. Isoform B: Widely expressed in tissues and also in breast cancer and in prostate carcinoma cells.

Similarity. Belongs to the adaptor complexes large subunit family.

Isoforms (2)

UniProt ID	Names	Canonical?
O95782-1	A	yes
O95782-2	B

RefSeq proteins (2): NP_055018, NP_570603* (*=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 (11 total): modified residue 4, sequence conflict 2, chain 1, region of interest 1, compositionally biased region 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95782-F1	84.78	0.67

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 (4): 626, 652, 653, 655

Function

Pathways and Gene Ontology

Reactome pathways

47 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-416993	Trafficking of GluR2-containing AMPA receptors
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-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-112314	Neurotransmitter receptors and postsynaptic signal transmission
R-HSA-112315	Transmission across Chemical Synapses
R-HSA-112316	Neuronal System
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-168256	Immune System
R-HSA-174824	Plasma lipoprotein assembly, remodeling, and clearance
R-HSA-187037	Signaling by NTRK1 (TRKA)

MSigDB gene sets: 275 (showing top): REACTOME_RETROGRADE_NEUROTROPHIN_SIGNALLING, GOBP_POLYSACCHARIDE_BIOSYNTHETIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GCM_GSPT1, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOCC_VACUOLAR_MEMBRANE, MODULE_264, GOBP_NEUROGENESIS, REACTOME_THE_ROLE_OF_NEF_IN_HIV_1_REPLICATION_AND_DISEASE_PATHOGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, GOBP_POSITIVE_REGULATION_OF_RECEPTOR_MEDIATED_ENDOCYTOSIS, GOBP_SYNAPTIC_VESICLE_RECYCLING

GO Biological Process (11): intracellular protein transport (GO:0006886), Golgi to endosome transport (GO:0006895), endocytosis (GO:0006897), positive regulation of neuron projection development (GO:0010976), vesicle-mediated transport (GO:0016192), positive regulation of receptor-mediated endocytosis (GO:0048260), synaptic vesicle endocytosis (GO:0048488), clathrin-dependent endocytosis (GO:0072583), postsynaptic neurotransmitter receptor internalization (GO:0098884), negative regulation of hyaluronan biosynthetic process (GO:1900126), protein transport (GO:0015031)

GO Molecular Function (5): protein kinase binding (GO:0019901), clathrin-cargo adaptor activity (GO:0035615), protein-containing complex binding (GO:0044877), low-density lipoprotein particle receptor binding (GO:0050750), protein binding (GO:0005515)

GO Cellular Component (21): cytosol (GO:0005829), plasma membrane (GO:0005886), synaptic vesicle (GO:0008021), cytoplasmic side of plasma membrane (GO:0009898), membrane (GO:0016020), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), AP-2 adaptor complex (GO:0030122), clathrin coat of trans-Golgi network vesicle (GO:0030130), endocytic vesicle membrane (GO:0030666), clathrin-coated endocytic vesicle membrane (GO:0030669), filopodium tip (GO:0032433), endolysosome membrane (GO:0036020), clathrin-coated endocytic vesicle (GO:0045334), postsynaptic endocytic zone (GO:0098843), glutamatergic synapse (GO:0098978), clathrin-coated pit (GO:0005905), membrane coat (GO:0030117), clathrin adaptor complex (GO:0030131), clathrin-coated vesicle (GO:0030136), protein-containing complex (GO:0032991)

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
Trafficking of AMPA receptors	1
L1CAM interactions	1
Clathrin-mediated endocytosis	1
Membrane Trafficking	1
SARS-CoV Infections	1
Dengue Virus Infection	1
Transmission across Chemical Synapses	1
Neuronal System	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
intracellular protein localization	2
transport	2
receptor-mediated endocytosis	2
binding	2
cytoplasm	2
membrane	2
plasma membrane region	2
endocytic vesicle	2
clathrin coat	2
protein transport	1
intracellular transport	1
post-Golgi vesicle-mediated transport	1
intercellular transport	1
cytosolic transport	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
cellular process	1
positive regulation of endocytosis	1
regulation of receptor-mediated endocytosis	1
synaptic vesicle recycling	1
presynaptic endocytosis	1
regulation of postsynaptic membrane neurotransmitter receptor levels	1
neurotransmitter receptor internalization	1
postsynaptic endocytosis	1
negative regulation of macromolecule biosynthetic process	1
hyaluronan biosynthetic process	1
negative regulation of carbohydrate metabolic process	1
regulation of hyaluronan biosynthetic process	1
establishment of protein localization	1
kinase binding	1
clathrin binding	1
cargo adaptor activity	1
lipoprotein particle receptor binding	1
cell periphery	1

Protein interactions and networks

STRING

2372 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AP2A1	AP2M1	P20172	984
AP2A1	AP2S1	P53680	963
AP2A1	AP2B1	P21851	944
AP2A1	NECAP1	Q8NC96	886
AP2A1	EPS15	P42566	850
AP2A1	CLTC	Q00610	847
AP2A1	NECAP2	Q9NVZ3	818
AP2A1	EPN1	Q9Y6I3	803
AP2A1	CLTB	P09497	793
AP2A1	CLTA	P09496	788
AP2A1	EPN2	O95208	780
AP2A1	CLTCL1	P53675	774
AP2A1	EPN3	Q9H201	753
AP2A1	SGIP1	Q9BQI5	730
AP2A1	TSKS	Q9UJT2	698

IntAct

205 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
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
STAMBP	PIK3C2A	psi-mi:“MI:0914”(association)	0.730
SHC1	AP2A1	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
EGFR	AP2A1	psi-mi:“MI:0914”(association)	0.670
AP2S1	AP2A2	psi-mi:“MI:0914”(association)	0.640
SF3B1	SAP18	psi-mi:“MI:0914”(association)	0.640
GPR156	PLD2	psi-mi:“MI:0914”(association)	0.640
OCRL	AP2A1	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
HIP1	AP2A1	psi-mi:“MI:0407”(direct interaction)	0.540
HIP1	AP2A1	psi-mi:“MI:0915”(physical association)	0.540
HIP1	AP2A1	psi-mi:“MI:0403”(colocalization)	0.540
AP2A1	HIP1	psi-mi:“MI:0403”(colocalization)	0.540
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

BioGRID (483): AP2A1 (Affinity Capture-MS), AP2A1 (Affinity Capture-MS), AP2A1 (Affinity Capture-MS), AP2A1 (Affinity Capture-MS), AP2A1 (Affinity Capture-MS), AP2A1 (Affinity Capture-MS), AP2A1 (Affinity Capture-MS), AP2A1 (Affinity Capture-MS), AP2A1 (Affinity Capture-MS), AP2A1 (Affinity Capture-MS), AP2A1 (Affinity Capture-MS), AP1B1 (Co-fractionation), AP2A1 (Co-fractionation), AP2A1 (Co-fractionation), AP2A1 (Co-fractionation)

ESM2 similar proteins: A0JN39, A8WGF4, B5DGH9, D2SW95, O00232, O60763, O95782, P17426, P23514, P41541, P53618, P91926, P93768, Q05AY2, Q0JNK5, Q1LUA8, Q29N38, Q2KJ25, Q3B8M3, Q3UGF1, Q4R4I8, Q53PC7, Q5R4J9, Q5R664, Q5R922, Q5RBI3, Q5VQ78, Q5XI83, Q5ZIA5, Q5ZLA5, Q66HV4, Q6DRI1, Q6H8D5, Q6H8D6, Q6N069, Q6NWV3, Q6P7L9, Q7QG73, Q80UM3, Q8BWQ6

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

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 217 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	7	35.1×	5e-08
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	6	25.0×	7e-06
The role of Nef in HIV-1 replication and disease pathogenesis	6	25.0×	7e-06
VLDLR internalisation and degradation	5	23.5×	9e-05
LDL clearance	5	17.9×	3e-04
Clathrin-mediated endocytosis	31	17.4×	2e-27
Cargo recognition for clathrin-mediated endocytosis	22	15.2×	1e-17
Golgi Associated Vesicle Biogenesis	11	14.5×	3e-08

GO biological processes:

GO term	Partners	Fold	FDR
clathrin coat assembly	10	47.2×	1e-12
synaptic vesicle endocytosis	14	32.2×	5e-15
clathrin-dependent endocytosis	10	30.9×	2e-10
regulation of endocytosis	5	12.8×	5e-03
positive regulation of protein localization to plasma membrane	7	10.1×	9e-04
positive regulation of fibroblast proliferation	6	9.4×	5e-03
regulation of protein localization	8	8.8×	6e-04
endocytosis	15	7.6×	5e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	108
Likely benign	3
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

3786 predictions. Top by Δscore:

Variant	Effect	Δscore
19:49781754:CAG:C	acceptor_loss	1.0000
19:49781755:A:T	acceptor_loss	1.0000
19:49781755:AG:A	acceptor_gain	1.0000
19:49781756:GG:G	acceptor_gain	1.0000
19:49781756:GGTA:G	acceptor_gain	1.0000
19:49781756:GGTAA:G	acceptor_gain	1.0000
19:49781824:AGGT:A	donor_loss	1.0000
19:49781826:G:GG	donor_gain	1.0000
19:49781826:GTA:G	donor_loss	1.0000
19:49781827:T:A	donor_loss	1.0000
19:49781939:T:TA	acceptor_gain	1.0000
19:49781944:TA:T	acceptor_loss	1.0000
19:49781945:A:AG	acceptor_gain	1.0000
19:49781945:AGG:A	acceptor_loss	1.0000
19:49781946:G:GA	acceptor_gain	1.0000
19:49781946:GGA:G	acceptor_gain	1.0000
19:49782057:T:G	donor_gain	1.0000
19:49782086:AATA:A	donor_gain	1.0000
19:49782090:G:GG	donor_gain	1.0000
19:49782525:CCACA:C	acceptor_loss	1.0000
19:49782526:CACA:C	acceptor_loss	1.0000
19:49782527:A:AG	acceptor_gain	1.0000
19:49782527:ACAG:A	acceptor_gain	1.0000
19:49782527:ACAGG:A	acceptor_gain	1.0000
19:49782528:CA:C	acceptor_loss	1.0000
19:49782529:A:AG	acceptor_gain	1.0000
19:49782529:AG:A	acceptor_gain	1.0000
19:49782529:AGG:A	acceptor_gain	1.0000
19:49782530:G:GC	acceptor_gain	1.0000
19:49782530:GG:G	acceptor_gain	1.0000

AlphaMissense

6232 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:49767167:G:A	G12R	1.000
19:49767167:G:C	G12R	1.000
19:49767167:G:T	G12W	1.000
19:49767168:G:A	G12E	1.000
19:49767171:T:A	L13H	1.000
19:49767171:T:C	L13P	1.000
19:49767179:T:A	F16I	1.000
19:49767179:T:C	F16L	1.000
19:49767180:T:C	F16S	1.000
19:49767180:T:G	F16C	1.000
19:49767181:C:A	F16L	1.000
19:49767181:C:G	F16L	1.000
19:49767183:T:A	I17N	1.000
19:49767183:T:C	I17T	1.000
19:49767183:T:G	I17S	1.000
19:49767185:T:C	S18P	1.000
19:49767188:G:C	D19H	1.000
19:49767189:A:T	D19V	1.000
19:49767192:T:A	I20N	1.000
19:49767192:T:G	I20S	1.000
19:49767195:G:C	R21P	1.000
19:49767200:T:C	C23R	1.000
19:49781757:G:A	C23Y	1.000
19:49781758:T:G	C23W	1.000
19:49781762:A:C	S25R	1.000
19:49781764:C:A	S25R	1.000
19:49781764:C:G	S25R	1.000
19:49781771:G:C	A28P	1.000
19:49781774:G:A	E29K	1.000
19:49781776:A:C	E29D	1.000

dbSNP variants (sampled 300 via entrez): RS1000002843 (19:49780492 G>A,C), RS1000084830 (19:49792606 A>G), RS1000201771 (19:49796749 CTA>C), RS1000299994 (19:49775192 C>T), RS1000454290 (19:49768970 C>T), RS1000499338 (19:49785363 G>A), RS1000542790 (19:49781037 C>T), RS1000552912 (19:49791941 C>T), RS1000637668 (19:49803514 G>A,C,T), RS1000651859 (19:49786045 A>G,T), RS1000801757 (19:49784952 C>T), RS1000826394 (19:49768609 T>A), RS1000915479 (19:49773191 C>T), RS1000988219 (19:49806362 C>A,T), RS1001007136 (19:49792585 C>T)

Disease associations

OMIM: gene MIM:601026 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90000025_572	Appendicular lean mass	7.000000e-20

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295687 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.70	Kd	199.7	nM	CHEMBL3752910
6.66	ED50	217.4	nM	CHEMBL3752910
5.36	Kd	4391	nM	CHEMBL5653589
5.32	ED50	4781	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 5 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147863: Binding affinity to human AP2A1 incubated for 45 mins by Kinobead based pull down assay	kd	0.1997	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147863: Binding affinity to human AP2A1 incubated for 45 mins by Kinobead based pull down assay	kd	4.3914	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects expression, decreases expression, increases expression, affects cotreatment, increases abundance (+1 more)	4
bisphenol A	increases expression	2
Arsenic	increases abundance, affects methylation, decreases expression	2
Ozone	affects cotreatment, increases oxidation, increases abundance, affects expression	2
Particulate Matter	increases abundance, increases expression, decreases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression, affects cotreatment	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
lead acetate	affects cotreatment, increases expression	1
tetrahydropalmatine	increases expression	1
zinc protoporphyrin	affects cotreatment, increases expression	1
sodium arsenite	increases abundance, decreases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
bis-N,N-dimethylamino-2-(N-methylpyrrolyl)methyl cyclopentadienyl titanium (IV)	decreases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Bortezomib	decreases expression	1
Acetaminophen	increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Dexamethasone	affects cotreatment, increases expression	1
Dinitrochlorobenzene	affects binding	1
Furaldehyde	affects cotreatment, decreases expression, affects localization, increases expression	1
Indomethacin	affects cotreatment, increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118997	Binding	Binding affinity to AP2A1 in human NCI-H358 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

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