AP2M1

adaptor related protein complex 2 subunit mu 1, the group of Adaptor related protein complex 2

Basic information

Region (hg38): 3:184174689-184184214

Previous symbols: [ "CLAPM1" ]

Links

ENSG00000161203 ∙ NCBI:1173 ∙ OMIM:601024 ∙ HGNC:564 ∙ Uniprot:Q96CW1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• intellectual developmental disorder 60 with seizures (Moderate), mode of inheritance: AD
• intellectual developmental disorder 60 with seizures (Strong), mode of inheritance: AD
• myoclonic-astatic epilepsy (Supportive), mode of inheritance: Unknown
• intellectual developmental disorder 60 with seizures (Moderate), mode of inheritance: AD
• intellectual developmental disorder 60 with seizures (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Intellectual developmental disorder, autosomal dominant 60, with seizures	AD	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Neurologic	31104773

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the AP2M1 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the AP2M1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				64	6	70
missense			56	4	2	62
nonsense			1			1
start loss						0
frameshift			3			3
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region			7	14	2	23
non coding			5	62	12	79
Total	0	0	65	130	20

Variants in AP2M1

This is a list of pathogenic ClinVar variants found in the AP2M1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
3-184176991-G-A			Likely benign (Mar 01, 2023)
3-184177017-TA-T			Uncertain significance (Jun 14, 2023)
3-184177023-C-T			Likely benign (Jul 12, 2022)
3-184177029-G-A			Likely benign (Jan 15, 2023)
3-184177035-G-C			Benign/Likely benign (Jan 19, 2025)
3-184177041-C-T			Likely benign (Oct 09, 2023)
3-184177043-C-T			Likely benign (Feb 02, 2022)
3-184177045-C-CGA			Uncertain significance (Aug 27, 2022)
3-184177048-G-A			Uncertain significance (Aug 31, 2023)
3-184177061-A-C			Uncertain significance (Nov 01, 2023)
3-184177066-G-A		Intellectual developmental disorder 60 with seizures	Uncertain significance (Nov 12, 2020)
3-184177073-T-C			Uncertain significance (Jul 05, 2022)
3-184177074-C-T			Likely benign (Mar 11, 2023)
3-184177081-C-T			Likely benign (May 27, 2024)
3-184177082-G-A			Likely benign (Sep 10, 2024)
3-184177552-G-T		AP2M1-related disorder	Likely benign (Aug 01, 2023)
3-184177576-T-C			Likely benign (Dec 01, 2024)
3-184177580-T-C		AP2M1-related disorder	Benign (Oct 30, 2019)
3-184178214-G-A			Likely benign (Jul 01, 2023)
3-184178837-T-G			Likely benign (Dec 30, 2023)
3-184178838-A-G			Benign (Dec 30, 2024)
3-184178839-T-C			Likely benign (Jun 03, 2023)
3-184178848-T-C			Likely benign (Aug 10, 2023)
3-184178850-C-A			Likely benign (Feb 17, 2024)
3-184178850-C-T			Likely benign (Aug 09, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
AP2M1	protein_coding	protein_coding	ENST00000292807	11	9403

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.999	0.000813	124794	0	2	124796	0.00000801

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.88	46	273	0.169	0.0000173	2890
Missense in Polyphen		9	104.41	0.086202		1213
Synonymous	1.34	85	102	0.832	0.00000646	824
Loss of Function	4.45	1	25.0	0.0400	0.00000151	261

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00000899	0.00000883
Middle Eastern	0.00	0.00
South Asian	0.0000328	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: 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. 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 'Tyr-156' in membrane- associated AP-2. The membrane-specific phosphorylation event appears to involve assembled clathrin which activates the AP-2 mu kinase AAK1 (By similarity). Plays a role in endocytosis of frizzled family members upon Wnt signaling (By similarity). {ECO:0000250, ECO:0000269|PubMed:12694563, ECO:0000269|PubMed:12952941, ECO:0000269|PubMed:14745134, ECO:0000269|PubMed:14985334, ECO:0000269|PubMed:15473838, ECO:0000269|PubMed:16581796, ECO:0000269|PubMed:19033387}.
• Pathway: Synaptic vesicle cycle - Homo sapiens (human);Endocytosis - Homo sapiens (human);Huntington,s disease - Homo sapiens (human);Endocrine and other factor-regulated calcium reabsorption - Homo sapiens (human);Synaptic Vesicle Pathway;GABA receptor Signaling;EGF-EGFR Signaling Pathway;Developmental Biology;Disease;Signaling by WNT;Signal Transduction;Recycling pathway of L1;Vesicle-mediated transport;endocytotic role of ndk phosphins and dynamin;Membrane Trafficking;Host Interactions of HIV factors;HIV Infection;MHC class II antigen presentation;Infectious disease;Immune System;LDL clearance;Ghrelin;VLDLR internalisation and degradation;Plasma lipoprotein clearance;Adaptive Immune System;Retrograde neurotrophin signalling;Transport of small molecules;Neuronal System;Clathrin-mediated endocytosis;Signaling by NTRK1 (TRKA);Nef mediated downregulation of CD28 cell surface expression;WNT5A-dependent internalization of FZD4;PCP/CE pathway;Signaling by NTRKs;Beta-catenin independent WNT signaling;-arrestins in gpcr desensitization;Nef Mediated CD4 Down-regulation;Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters;The role of Nef in HIV-1 replication and disease pathogenesis;Arf1 pathway;Plasma lipoprotein assembly, remodeling, and clearance;Cargo recognition for clathrin-mediated endocytosis;Trafficking of GluR2-containing AMPA receptors;Trafficking of AMPA receptors;L1CAM interactions;Glutamate binding, activation of AMPA receptors and synaptic plasticity;Neurotransmitter receptors and postsynaptic signal transmission;Transmission across Chemical Synapses;Axon guidance;Signaling by Receptor Tyrosine Kinases;Formation of annular gap junctions;Gap junction degradation;Gap junction trafficking;Gap junction trafficking and regulation;Nef Mediated CD8 Down-regulation (Consensus)

Recessive Scores

• pRec: 0.247

Intolerance Scores

• loftool: 0.206
• rvis_EVS: -0.14
• rvis_percentile_EVS: 42.88

Haploinsufficiency Scores

• pHI: 0.237
• hipred: Y
• hipred_score: 0.783
• ghis: 0.645

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: K
• gene_indispensability_pred: E
• gene_indispensability_score: 0.945

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Ap2m1
• Phenotype: mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cellular phenotype

Gene ontology

• Biological process: intracellular protein transport;vesicle budding from membrane;antigen processing and presentation of exogenous peptide antigen via MHC class II;receptor internalization;low-density lipoprotein particle receptor catabolic process;low-density lipoprotein particle clearance;ephrin receptor signaling pathway;regulation of defense response to virus by virus;Wnt signaling pathway, planar cell polarity pathway;membrane organization;clathrin-dependent endocytosis;regulation of vesicle size;negative regulation of protein localization to plasma membrane
• Cellular component: lysosomal membrane;cytosol;plasma membrane;AP-2 adaptor complex;endocytic vesicle membrane;clathrin-coated endocytic vesicle membrane;endolysosome membrane;clathrin-coated endocytic vesicle;extracellular exosome
• Molecular function: signal sequence binding;transporter activity;protein binding;lipid binding;clathrin adaptor activity;ion channel binding;low-density lipoprotein particle receptor binding