AP2M1

Summary

AP2M1 (adaptor related protein complex 2 subunit mu 1, HGNC:564) is a protein-coding gene on chromosome 3q27.1, encoding AP-2 complex subunit mu (Q96CW1). Component of the adaptor protein complex 2 (AP-2). It is a selective cancer dependency (DepMap: 76.0% of cell lines).

This gene encodes a subunit of the heterotetrameric coat assembly protein complex 2 (AP2), which belongs to the adaptor complexes medium subunits family. The encoded protein is required for the activity of a vacuolar ATPase, which is responsible for proton pumping occurring in the acidification of endosomes and lysosomes. The encoded protein may also play an important role in regulating the intracellular trafficking and function of CTLA-4 protein. Three transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 1173 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 320 total
• Phenotypes (HPO): 57
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 76.0% of screened cell lines
• MANE Select transcript: NM_004068

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:564
Approved symbol	AP2M1
Name	adaptor related protein complex 2 subunit mu 1
Location	3q27.1
Locus type	gene with protein product
Status	Approved
Aliases	AP50, mu2
Ensembl gene	ENSG00000161203
Ensembl biotype	protein_coding
OMIM	601024
Entrez	1173

Gene structure

Transcript identifiers

Ensembl transcripts: 45 — 22 protein_coding, 18 retained_intron, 4 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000292807, ENST00000382456, ENST00000411763, ENST00000427072, ENST00000431779, ENST00000432591, ENST00000439647, ENST00000442686, ENST00000448139, ENST00000455925, ENST00000460862, ENST00000461733, ENST00000463935, ENST00000466598, ENST00000468048, ENST00000472560, ENST00000476434, ENST00000480260, ENST00000484469, ENST00000487958, ENST00000490151, ENST00000621863, ENST00000684853, ENST00000685290, ENST00000685698, ENST00000686364, ENST00000686942, ENST00000687623, ENST00000688579, ENST00000688830, ENST00000690285, ENST00000692019, ENST00000692162, ENST00000693186, ENST00000895675, ENST00000895676, ENST00000895677, ENST00000938086, ENST00000938087, ENST00000938088, ENST00000938089, ENST00000938090, ENST00000938091, ENST00000963226, ENST00000963227

RefSeq mRNA: 3 — MANE Select: NM_004068 NM_001025205, NM_001311198, NM_004068

CCDS: CCDS43177, CCDS43178, CCDS82880

Canonical transcript exons

ENST00000292807 — 12 exons

Exon	Start	End
ENSE00001315581	184183482	184184091
ENSE00001673656	184174855	184174959
ENSE00003539744	184181696	184181815
ENSE00003543420	184181912	184182047
ENSE00003564450	184182757	184182868
ENSE00003569595	184182151	184182248
ENSE00003596628	184180849	184180984
ENSE00003618831	184181085	184181226
ENSE00003673476	184176951	184177067
ENSE00003677795	184180645	184180650
ENSE00003693024	184180169	184180251
ENSE00003785534	184178857	184179122

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 99.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 189.5967 / max 2415.4177, expressed in 1828 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
40132	187.0765	1828
40133	0.9868	507
40134	0.9472	595
40138	0.2785	113
40136	0.2693	82
203049	0.0222	9
40137	0.0162	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	99.58	gold quality
prefrontal cortex	UBERON:0000451	99.54	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.50	gold quality
right adrenal gland	UBERON:0001233	99.49	gold quality
right adrenal gland cortex	UBERON:0035827	99.49	gold quality
stromal cell of endometrium	CL:0002255	99.48	gold quality
left adrenal gland	UBERON:0001234	99.45	gold quality
left adrenal gland cortex	UBERON:0035825	99.44	gold quality
cerebellar hemisphere	UBERON:0002245	99.43	gold quality
cerebellar cortex	UBERON:0002129	99.41	gold quality
cingulate cortex	UBERON:0003027	99.35	gold quality
ganglionic eminence	UBERON:0004023	99.34	gold quality
cortical plate	UBERON:0005343	99.34	gold quality
anterior cingulate cortex	UBERON:0009835	99.34	gold quality
adenohypophysis	UBERON:0002196	99.30	gold quality
adrenal gland	UBERON:0002369	99.29	gold quality
adrenal cortex	UBERON:0001235	99.28	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.25	gold quality
metanephros cortex	UBERON:0010533	99.24	gold quality
lower esophagus	UBERON:0013473	99.23	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.23	gold quality
endocervix	UBERON:0000458	99.21	gold quality
frontal cortex	UBERON:0001870	99.21	gold quality
frontal lobe	UBERON:0016525	99.21	gold quality
pituitary gland	UBERON:0000007	99.20	gold quality
body of uterus	UBERON:0009853	99.18	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.17	gold quality
apex of heart	UBERON:0002098	99.16	gold quality
ventricular zone	UBERON:0003053	99.16	gold quality
muscle layer of sigmoid colon	UBERON:0035805	99.16	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	11.17
E-HCAD-11	yes	6.33
E-MTAB-7052	no	856.07
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR

miRNA regulators (miRDB)

43 targeting AP2M1, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6870-5P	99.99	68.55	2115
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-6825-5P	99.96	69.81	3431
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-3156-3P	99.76	66.72	939
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-3177-5P	99.65	70.38	1174
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-6839-3P	99.39	68.86	1301
HSA-MIR-4797-5P	99.39	68.01	1354
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-5587-5P	99.07	68.58	838
HSA-MIR-629-5P	98.78	68.72	1032
HSA-MIR-519A-2-5P	98.78	71.74	1401
HSA-MIR-520B-5P	98.78	71.74	1401
HSA-MIR-548Q	98.71	65.35	563
HSA-MIR-193A-3P	98.59	66.36	769
HSA-MIR-193B-3P	98.59	66.62	748

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 76.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 31)

• V1H can function as an adaptor for interactions between Nef and AP-2. (PMID:12032142)
• direct association of the adaptor complex 2 with a G protein-coupled receptor has not been reported so far and might represent a common mechanism underlying clathrin-mediated receptor endocytosis (PMID:12644451)
• Results indicate that AP-2 is not essential for clathrin-coated vesicle formation at the plasma membrane, but that it is one of several endocytic adaptors required for the uptake of certain cargo proteins. (PMID:12952941)
• AP-2 is completely dependent on both (D/E)xxxL(L/I) motifs and 20 YxxO motifs signals to mediate TCR internalization; AP2M1 interacts with tyrosine in CD3delta and CD3gamma (PMID:15778375)
• AP-2 and clathrin participate in MHC-II molecule trafficking to antigen-processing compartments. (PMID:15911768)
• We show that in addition to promoting LPA(1) signaling, membrane cholesterol is essential for the association of LPA(1) with beta-arrestin, which leads to signal attenuation and clathrin-dependent endocytosis of LPA(1). (PMID:16263766)
• Phosphorylation of AP-2 mu2 subunit is essential for Na+,K+-ATPase endocytosis in response to a variety of signals, such as dopamine or reactive oxygen species. (PMID:16498080)
• The essential GYxxtheta motif in the HIV-2 Env tail recruits AP-2 in order to direct Env to a cellular pathway or location that is necessary for its ability to enhance virus release. (PMID:16501101)
• there is a positive feedback loop consisting of endocytic cargo proteins, AP-2mu, and PIPK type I which may provide a specific pool of PI(4,5)P(2) dedicated to clathrin/AP-2-dependent receptor internalization (PMID:16880396)
• An atypical basic motif within the cytoplasmic tails of AMPA-type glutamate receptors directly associates with mu2-adaptin by a mechanism similar to the recognition of the presynaptic vesicle protein synaptotagmin 1 by AP-2. (PMID:17289840)
• Results show that three genes, namely FXR1, CLAPM1 and EIF4G, are most frequently overexpressed in the center of the amplified domain in squamous cell carcinomas. (PMID:17290396)
• These results thus identify a novel type of AP-2 interaction determinant, support the notion that AP-2 is the key clathrin adaptor for the downregulation of CD4 by Nef, and reveal a previously unrecognized diversity among dileucine sorting signals. (PMID:18032517)
• These findings demonstrate differences in internalization between the alpha1a- and alpha1b-AR and provide evidence that the lack of significant endocytosis of the alpha1a-AR is linked to its poor interaction with beta-arrestins as well as with AP50. (PMID:18523139)
• The dyslexia-associated protein KIAA0319 interacts with adaptor protein 2 and follows the classical clathrin-mediated endocytosis pathway. (PMID:19419997)
• multiple interactions between PIPKI gamma-p90 and AP-2 lead to spatiotemporally controlled PI(4,5)P(2) synthesis during clathrin-mediated synaptic vesicle endocytosis. (PMID:19903820)
• These results suggest that AP-2 is essential for endocytic clathrin coated-pit and coated-vesicle formation. (PMID:20485680)
• Arkadia complexes with clathrin adaptor AP2 mu2 subunit and regulates EGF signalling. (PMID:20965945)
• a conserved heretofore unrecognized YXXPhi motif (Phi is a bulky hydrophobic residue) within the core protein. This motif is homologous to sorting signals within host cargo proteins known to mediate binding of AP2M1 (PMID:22916011)
• We identify dynamin and the EAP-binding alpha-adaptin appendage domain of the AP2 adaptor as switches in a regulated, multistep maturation process and provide direct evidence for a molecular checkpoint in clathrin mediated endocytosis. (PMID:23891661)
• BMCC1 is an AP-2 associated endosomal protein in prostate cancer cells. (PMID:24040105)
• This study identified and confirmed adaptor protein 2 changes within the postsynaptic density in schizophrenia. (PMID:25048004)
• 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)
• It has been shown that the cytoplasmic domains of furin bind the mu subunits of AP-1 and AP-2 in a phosphorylation-dependent manner. (PMID:30135209)
• AP2M1 expression values fulfills a sufficient role as a novel prognostic marker for hepatocellular carcinoma, especially in, alcohol or hepatitis C subgroups. (PMID:30260026)
• A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy. (PMID:31104773)
• The knockdown of AP2M1 in the Dengue virus infected Huh7 cells displayed a reduction in the viral titer at 24 h post-infection. (PMID:31720911)
• Expression levels of SIX1, ME2, and AP2M1 in adenoid cystic carcinoma and mucoepidermoid carcinoma. (PMID:32564485)
• Regulation of BMP2K in AP2M1-mediated EGFR internalization during the development of gallbladder cancer. (PMID:32792513)
• AP2M1 mediates autophagy-induced CLDN2 (claudin 2) degradation through endocytosis and interaction with LC3 and reduces intestinal epithelial tight junction permeability. (PMID:34964704)
• High expression of AP2M1 correlates with worse prognosis by regulating immune microenvironment and drug resistance to R-CHOP in diffuse large B cell lymphoma. (PMID:36335584)
• SLC26A4-AP-2 mu2 interaction regulates SLC26A4 plasma membrane abundance in the endolymphatic sac. (PMID:39383236)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ap2m1a	ENSDARG00000002790
danio_rerio	ap2m1b	ENSDARG00000033899
mus_musculus	Ap2m1	ENSMUSG00000022841
rattus_norvegicus	Ap2m1	ENSRNOG00000001709

Paralogs (7): AP3M2 (ENSG00000070718), AP1M1 (ENSG00000072958), AP1M2 (ENSG00000129354), STON2 (ENSG00000140022), AP3M1 (ENSG00000185009), AP4M1 (ENSG00000221838), STON1 (ENSG00000243244)

Protein

Protein identifiers

AP-2 complex subunit mu — Q96CW1 (reviewed: Q96CW1)

Alternative names: AP-2 mu chain, Adaptin-mu2, Adaptor protein complex AP-2 subunit mu, Adaptor-related protein complex 2 subunit mu, Clathrin assembly protein complex 2 mu medium chain, Clathrin coat assembly protein AP50, Clathrin coat-associated protein AP50, HA2 50 kDa subunit, Plasma membrane adaptor AP-2 50 kDa protein

All UniProt accessions (13): A0A087WY71, A0A8I5KT55, A0A8I5KTP2, A0A8I5KWD3, A0A8I5QJU5, C9JGT8, C9JJ47, C9JJD3, C9JPV8, C9JTK4, Q96CW1, E9PFW3, H7C4C3

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 mu subunit binds to transmembrane cargo proteins; it recognizes the Y-X-X-Phi motifs. The surface region interacting with to the Y-X-X-Phi motif is inaccessible in cytosolic AP-2, but becomes accessible through a conformational change following phosphorylation of AP-2 mu subunit at Thr-156 in membrane-associated AP-2. The membrane-specific phosphorylation event appears to involve assembled clathrin which activates the AP-2 mu kinase AAK1. Plays a role in endocytosis of frizzled family members upon Wnt signaling.

Subunit / interactions. Adapter 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 ATP6V1H and MEGF10. Interacts with EGFR and TTGN1. Interacts with F2R. Interacts with PIP5K1C; tyrosine phosphorylation of PIP5K1C weakens the interaction. Interacts with KIAA0319; required for clathrin-mediated endocytosis of KIAA0319. Interacts with DVL2 (via DEP domain). Interacts with KCNQ1; mediates estrogen-induced internalization via clathrin-coated vesicles. Interacts with P2RX4 (via internalization motif). Together with AP2A1 or AP2A2 and AP2B1, it interacts with ADAM10; this interaction facilitates ADAM10 endocytosis from the plasma membrane during long-term potentiation in hippocampal neurons. Probably interacts with ACE2 (via endocytic sorting signal motif); the interaction is inhibited by ACE2 phosphorylation. Interacts with RALBP1; the interaction is direct. Interacts with TMEM106B (via N-terminus).

Subcellular location. Cell membrane. Membrane. Coated pit.

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

Post-translational modifications. Phosphorylation at Thr-156 increases the affinity of the AP-2 complex for cargo membrane proteins during the initial stages of endocytosis.

Disease relevance. Intellectual developmental disorder, autosomal dominant 60, with seizures (MRD60) [MIM:618587] An autosomal dominant disorder characterized by global developmental delay apparent in the first six months of life, followed by onset of seizures between 21 months and 4 years. Disease features include moderate-to-severe intellectual disability, poor speech, delayed walking, and ataxia. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the adaptor complexes medium subunit family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96CW1-1	1	yes
Q96CW1-2	2

RefSeq proteins (3): NP_001020376, NP_001298127, NP_004059* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001392	Clathrin_mu	Family
IPR011012	Longin-like_dom_sf	Homologous_superfamily
IPR018240	Clathrin_mu_CS	Conserved_site
IPR022775	AP_mu_sigma_su	Domain
IPR028565	MHD	Domain
IPR036168	AP2_Mu_C_sf	Homologous_superfamily
IPR043512	Mu2_C	Domain
IPR043532	AP2_Mu_N	Domain
IPR050431	Adaptor_comp_med_subunit	Family

Pfam: PF00928, PF01217

UniProt features (38 total): strand 21, helix 5, binding site 3, turn 2, modified residue 2, chain 1, domain 1, splice variant 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6URI	X-RAY DIFFRACTION	3
6BNT	X-RAY DIFFRACTION	3.2
1H6E	X-RAY DIFFRACTION	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96CW1-F1	89.44	0.72

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): 341; 345; 354

Post-translational modifications (2): 45, 156

Function

Pathways and Gene Ontology

Reactome pathways

47 pathways

ID	Pathway
R-HSA-164939	Nef mediated downregulation of CD28 cell surface expression
R-HSA-167590	Nef Mediated CD4 Down-regulation
R-HSA-177504	Retrograde neurotrophin signalling
R-HSA-182218	Nef Mediated CD8 Down-regulation
R-HSA-190873	Gap junction degradation
R-HSA-196025	Formation of annular gap junctions
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-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-157858	Gap junction trafficking and regulation
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

MSigDB gene sets: 434 (showing top): REACTOME_RETROGRADE_NEUROTROPHIN_SIGNALLING, MORF_MBD4, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOCC_VACUOLAR_MEMBRANE, GOBP_VESICLE_ORGANIZATION, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, MORF_UBE2I, DITTMER_PTHLH_TARGETS_UP, GOBP_VACUOLAR_TRANSPORT, MODULE_264, REACTOME_THE_ROLE_OF_NEF_IN_HIV_1_REPLICATION_AND_DISEASE_PATHOGENESIS, TGACCTY_ERR1_Q2, GOBP_VESICLE_MEDIATED_TRANSPORT

GO Biological Process (15): positive regulation of receptor internalization (GO:0002092), intracellular protein transport (GO:0006886), vesicle budding from membrane (GO:0006900), vesicle-mediated transport (GO:0016192), receptor internalization (GO:0031623), synaptic vesicle endocytosis (GO:0048488), protein-containing complex assembly (GO:0065003), clathrin-dependent endocytosis (GO:0072583), regulation of vesicle size (GO:0097494), postsynaptic neurotransmitter receptor internalization (GO:0098884), positive regulation of synaptic vesicle endocytosis (GO:1900244), negative regulation of protein localization to plasma membrane (GO:1903077), endocytosis (GO:0006897), protein transport (GO:0015031), vesicle-mediated transport in synapse (GO:0099003)

GO Molecular Function (7): signal sequence receptor activity (GO:0005048), lipid binding (GO:0008289), clathrin-cargo adaptor activity (GO:0035615), transmembrane transporter binding (GO:0044325), low-density lipoprotein particle receptor binding (GO:0050750), disordered domain specific binding (GO:0097718), protein binding (GO:0005515)

GO Cellular Component (20): lysosomal membrane (GO:0005765), cytosol (GO:0005829), plasma membrane (GO:0005886), clathrin-coated pit (GO:0005905), synaptic vesicle (GO:0008021), cytoplasmic side of plasma membrane (GO:0009898), AP-2 adaptor complex (GO:0030122), endocytic vesicle membrane (GO:0030666), clathrin-coated endocytic vesicle membrane (GO:0030669), cytoplasmic vesicle (GO:0031410), endolysosome membrane (GO:0036020), clathrin-coated endocytic vesicle (GO:0045334), extracellular exosome (GO:0070062), postsynapse (GO:0098794), extrinsic component of presynaptic endocytic zone membrane (GO:0098894), glutamatergic synapse (GO:0098978), cytoplasm (GO:0005737), membrane (GO:0016020), clathrin adaptor complex (GO:0030131), synapse (GO:0045202)

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	3
PCP/CE pathway	2
Plasma lipoprotein clearance	2
Signaling by NTRK1 (TRKA)	1
Gap junction trafficking	1
Gap junction degradation	1
Adaptive Immune System	1
EPH-Ephrin signaling	1
L1CAM interactions	1
Clathrin-mediated endocytosis	1
Membrane Trafficking	1
SARS-CoV Infections	1
Dengue Virus Infection	1
Trafficking of AMPA receptors	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
vesicle-mediated transport	3
synapse	3
intracellular protein localization	2
transport	2
receptor-mediated endocytosis	2
binding	2
cytoplasm	2
membrane	2
endocytic vesicle	2
regulation of receptor internalization	1
receptor internalization	1
positive regulation of receptor-mediated endocytosis	1
protein transport	1
intracellular transport	1
vesicle organization	1
membrane organization	1
cellular process	1
synaptic vesicle recycling	1
presynaptic endocytosis	1
cellular component assembly	1
protein-containing complex organization	1
regulation of cellular component size	1
regulation of postsynaptic membrane neurotransmitter receptor levels	1
neurotransmitter receptor internalization	1
postsynaptic endocytosis	1
positive regulation of endocytosis	1
synaptic vesicle endocytosis	1
regulation of synaptic vesicle endocytosis	1
positive regulation of synaptic vesicle recycling	1
protein localization to plasma membrane	1
regulation of protein localization to plasma membrane	1
negative regulation of protein localization to cell periphery	1
negative regulation of protein localization to membrane	1
vesicle budding from membrane	1
membrane invagination	1
import into cell	1
establishment of protein localization	1
molecular_function	1
clathrin binding	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

361 interactions, top by confidence:

A	B	Type	Score
GRB2	EGFR	psi-mi:“MI:0914”(association)	0.980
ATG9A	AP2M1	psi-mi:“MI:0407”(direct interaction)	0.890
AP2M1	ATG9A	psi-mi:“MI:0407”(direct interaction)	0.890
EGFR	AP2M1	psi-mi:“MI:0915”(physical association)	0.830
AP2M1	AP2B1	psi-mi:“MI:0915”(physical association)	0.810
AP2M1	TBC1D5	psi-mi:“MI:0915”(physical association)	0.740
TBC1D5	AP2M1	psi-mi:“MI:0407”(direct interaction)	0.740
AP2M1	RSPH14	psi-mi:“MI:0915”(physical association)	0.670
UTP25	AP2M1	psi-mi:“MI:0915”(physical association)	0.670
rep	AP2A2	psi-mi:“MI:0914”(association)	0.660
AP2M1	FXR2	psi-mi:“MI:0915”(physical association)	0.650
ZNF581	AP2M1	psi-mi:“MI:0915”(physical association)	0.560
KNOP1	AP2M1	psi-mi:“MI:0915”(physical association)	0.560
HEXIM2	AP2M1	psi-mi:“MI:0915”(physical association)	0.560
	AP2M1	psi-mi:“MI:0915”(physical association)	0.560
H2BC10	AP2M1	psi-mi:“MI:0915”(physical association)	0.560
PRPF38A	AP2M1	psi-mi:“MI:0915”(physical association)	0.560
FAM90A1	AP2M1	psi-mi:“MI:0915”(physical association)	0.560
AP2M1	H2BC13	psi-mi:“MI:0915”(physical association)	0.560
PTS	AP2M1	psi-mi:“MI:0915”(physical association)	0.560
AP2M1	PRPF18	psi-mi:“MI:0915”(physical association)	0.560
AP2M1	MMTAG2	psi-mi:“MI:0915”(physical association)	0.560
MTURN	AP2M1	psi-mi:“MI:0915”(physical association)	0.560
H2BC21	AP2M1	psi-mi:“MI:0915”(physical association)	0.560
NKAPD1	AP2M1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (797): CORO7 (Protein-peptide), AP2M1 (Affinity Capture-MS), AP2M1 (Affinity Capture-MS), AP2M1 (Affinity Capture-MS), AP2S1 (Affinity Capture-MS), AP2A2 (Affinity Capture-MS), AP2A1 (Affinity Capture-MS), AP1S2 (Affinity Capture-MS), AP1S1 (Affinity Capture-MS), AP1S3 (Affinity Capture-MS), BCR (Affinity Capture-MS), AMER1 (Affinity Capture-MS), BMP2K (Affinity Capture-MS), AAK1 (Affinity Capture-MS), SPECC1L (Affinity Capture-MS)

ESM2 similar proteins: A0CDD4, D3ZRP6, O22715, O23140, P35585, P35602, P35603, P35615, P48454, P53027, P53619, P59780, P62495, P62496, P62497, P62498, P84091, P84092, Q0VCX5, Q1JQA3, Q24208, Q2KJ81, Q32Q06, Q3SYW1, Q3ZC13, Q4R706, Q5NVF7, Q5R4C7, Q5RDP9, Q5U2Q7, Q5XJY5, Q5ZL57, Q5ZMP6, Q66H80, Q6NWK2, Q6P856, Q6PC69, Q7ZW98, Q801Q8, Q8BSZ2

Diamond homologs: D3ZRP6, O22715, O23140, P35585, P35602, P35603, P54672, P84091, P84092, Q00776, Q09718, Q24212, Q2KJ81, Q32Q06, Q3SYW1, Q3ZC13, Q4R706, Q54HS9, Q5NVF7, Q5ZMP6, Q5ZMP7, Q6NWK2, Q6P856, Q7ZW98, Q801Q8, Q96CW1, Q9BXS5, Q9GPF1, Q9HFE5, Q9SAC9, Q9SB50, Q9WVP1, Q9Y6Q5, Q99186, Q750L8, Q8CDJ8, F4I562, Q3ZBB6, E2RED8, Q29RY8

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
AAK1	up-regulates	AP2M1	phosphorylation
RNF111	up-regulates	AP2M1	ubiquitination
AP2M1	down-regulates	EGFR	relocalization
AP2M1	“down-regulates quantity”	SLC24A2	binding
LRRK2	“up-regulates activity”	AP2M1	phosphorylation
AP2M1	“form complex”	“AP-2 complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 126 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
Cargo recognition for clathrin-mediated endocytosis	12	17.5×	9e-10
Clathrin-mediated endocytosis	14	16.6×	5e-11
Potential therapeutics for SARS	8	12.7×	4e-05
Signaling by NTRKs	5	12.6×	2e-03
Extra-nuclear estrogen signaling	5	11.8×	3e-03
EPH-Ephrin signaling	5	11.5×	3e-03
Signaling by ALK fusions and activated point mutants	5	10.4×	4e-03
Constitutive Signaling by Aberrant PI3K in Cancer	5	8.8×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of fibroblast proliferation	5	15.4×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	107
Likely benign	164
Benign	23

Top pathogenic / likely-pathogenic (0)

SpliceAI

1755 predictions. Top by Δscore:

Variant	Effect	Δscore
3:184177066:GG:G	donor_gain	1.0000
3:184177067:GG:G	donor_gain	1.0000
3:184177067:GGTG:G	donor_loss	1.0000
3:184177068:G:GG	donor_gain	1.0000
3:184177068:GTGAG:G	donor_loss	1.0000
3:184177069:T:A	donor_loss	1.0000
3:184177070:GAG:G	donor_loss	1.0000
3:184178853:TCAG:T	acceptor_loss	1.0000
3:184178854:CA:C	acceptor_loss	1.0000
3:184178855:A:AG	acceptor_gain	1.0000
3:184178855:A:AT	acceptor_loss	1.0000
3:184178855:AG:A	acceptor_gain	1.0000
3:184178855:AGGAG:A	acceptor_gain	1.0000
3:184178856:G:GT	acceptor_gain	1.0000
3:184178856:GG:G	acceptor_gain	1.0000
3:184178856:GGA:G	acceptor_gain	1.0000
3:184178856:GGAGG:G	acceptor_gain	1.0000
3:184179077:G:GT	donor_gain	1.0000
3:184179078:A:T	donor_gain	1.0000
3:184179118:GGATG:G	donor_gain	1.0000
3:184179119:GATG:G	donor_gain	1.0000
3:184179119:GATGG:G	donor_gain	1.0000
3:184179121:TGGTG:T	donor_loss	1.0000
3:184179123:G:GA	donor_loss	1.0000
3:184179124:T:A	donor_loss	1.0000
3:184180164:TGCA:T	acceptor_loss	1.0000
3:184180166:CAGA:C	acceptor_loss	1.0000
3:184180167:A:AG	acceptor_gain	1.0000
3:184180168:G:GC	acceptor_gain	1.0000
3:184180168:GA:G	acceptor_gain	1.0000

AlphaMissense

2897 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:184177004:G:A	G4D	1.000
3:184177020:T:A	N9K	1.000
3:184177020:T:G	N9K	1.000
3:184177027:G:A	G12R	1.000
3:184177027:G:C	G12R	1.000
3:184177027:G:T	G12W	1.000
3:184177028:G:A	G12E	1.000
3:184177028:G:T	G12V	1.000
3:184177037:T:C	L15P	1.000
3:184177046:G:C	R18P	1.000
3:184177055:G:C	R21P	1.000
3:184178877:T:C	F32S	1.000
3:184178880:G:C	R33P	1.000
3:184178889:T:A	V36D	1.000
3:184178922:T:A	V47D	1.000
3:184178972:T:A	W64R	1.000
3:184178972:T:C	W64R	1.000
3:184179095:T:C	F105L	1.000
3:184179097:T:A	F105L	1.000
3:184179097:T:G	F105L	1.000
3:184179110:G:A	E110K	1.000
3:184179114:T:C	L111P	1.000
3:184179117:T:C	L112P	1.000
3:184179119:G:C	D113H	1.000
3:184179120:A:T	D113V	1.000
3:184180183:G:C	G119R	1.000
3:184180184:G:A	G119D	1.000
3:184180184:G:T	G119V	1.000
3:184180214:T:C	L129P	1.000
3:184180900:T:A	W161R	1.000

dbSNP variants (sampled 300 via entrez): RS1000083186 (3:184182521 G>C,T), RS1000299976 (3:184173604 TATTATTATTATTTTATC>T), RS1000680974 (3:184183954 C>T), RS1000732874 (3:184183686 C>A,G,T), RS1000804653 (3:184176813 G>A), RS1001472327 (3:184179664 T>C), RS1001798107 (3:184175811 C>G), RS1002081301 (3:184175519 G>T), RS1002889645 (3:184176746 A>G), RS1003277476 (3:184175103 A>C), RS1003475359 (3:184177313 C>A), RS1003753822 (3:184176977 G>A,T), RS1004044570 (3:184175088 T>A), RS1004102942 (3:184183824 C>T), RS1004331300 (3:184174931 C>T)

Disease associations

OMIM: gene MIM:601024 | disease phenotypes: MIM:618587

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual developmental disorder 60 with seizures	Strong	Autosomal dominant
myoclonic-astatic epilepsy	Supportive	Unknown

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (4): neurodevelopmental disorder (MONDO:0700092), intellectual developmental disorder 60 with seizures (MONDO:0032823), complex neurodevelopmental disorder (MONDO:0100038), (MONDO:0016025)

Orphanet (1): Non-specific syndromic intellectual disability (Orphanet:528084)

HPO phenotypes

57 total (30 of 57 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000154	Wide mouth
HP:0000179	Thick lower lip vermilion
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000289	Broad philtrum
HP:0000343	Long philtrum
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000568	Microphthalmia
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0001159	Syndactyly
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001326	EEG with irregular generalized spike and wave complexes
HP:0001336	Myoclonus
HP:0001337	Tremor
HP:0001999	Abnormal facial shape
HP:0002066	Gait ataxia
HP:0002069	Bilateral tonic-clonic seizure
HP:0002072	Chorea
HP:0002078	Truncal ataxia
HP:0002121	Generalized non-motor (absence) seizure
HP:0002123	Generalized myoclonic seizure
HP:0002292	Frontal balding

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001469_1	Major depressive disorder	5.000000e-06

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067156 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 3 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.29	Kd	5131	nM	CHEMBL3752910
5.29	ED50	5131	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 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	2147866: Binding affinity to human AP2M1 incubated for 45 mins by Kinobead based pull down assay	kd	5.1305	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	3
bisphenol A	affects cotreatment, increases methylation, increases expression	2
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	2
Acrolein	affects cotreatment, increases oxidation, increases abundance	2
Ozone	affects cotreatment, increases oxidation, increases abundance	2
Cyclosporine	decreases expression	2
Particulate Matter	increases expression, decreases expression, increases abundance	2
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
cobaltous chloride	decreases expression	1
coumarin	increases phosphorylation	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
azoxystrobin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
CD 437	decreases expression	1
deguelin	decreases expression	1
3-(4’-hydroxy-3’-adamantylbiphenyl-4-yl)acrylic acid	decreases expression	1
bisphenol B	increases expression	1
nilotinib	affects expression, affects cotreatment	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	affects cotreatment, affects expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Arsenic	decreases expression, increases abundance	1
Atrazine	increases expression	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
CHEMBL5650908	Binding	Binding affinity to human AP2M1 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

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E1K8	HyCyte HEK293T KO-hAP2M1	Transformed cell line	Female
CVCL_SC78	HAP1 AP2M1 (-) 1	Cancer cell line	Male
CVCL_SC79	HAP1 AP2M1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice