AP2M1

protein-coding

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

Gene summary

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. [provided by RefSeq, Jul 2015]

Previous symbols:

CLAPM1

MANE transcript

NM_004068.4

Inheritance

ClinVar variants

P:2U:105B:94

Top phenotype

Intellectual developmental disorder, autosomal dominant 60, with seizures

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr3:184,174,689-184,184,214

External References & Databases

Ensembl (ENSG00000161203)

Transcript & Mutation Effects

hg38 • Region Span ~9.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*AP2M1* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2019 (Helbig et al., PMID:31104773). The phenotype includes global developmental delay and intellectual disability, often associated with seizures, hypotonia, ataxia, and/or autism. Nine missense variants and one splice site variant have been reported in 14 probands from 9 publications (PMIDs: 36553572, 31104773, 37838930, 33057194, 31785789, 35982159, 28714951, 35982160, 37393044), all of which are included in this curation. The recurrent c.508C>T (p.Arg170Trp) variant has been identified as a de novo variant in five probands including four individuals with developmental and epileptic encephalopathy (DEE) (PMID:31104773, 37393044). The mechanism of pathogenicity is currently unknown. In summary, there is definitive evidence supporting the relationship between *AP2M1* and autosomal dominant neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Epilepsy GCEP on the meeting date October 1, 2024 (SOP Version 11). As of November 24, 2025, this record underwent administrative updates to fix a scoring error. No new evidence has been reviewed or added and the classification did not change.

intellectual developmental disorder 60 with seizuresMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032823

Submitter: Ambry Genetics

myoclonic-astatic epilepsySUPPORTIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0016025

Submitter: Orphanet

intellectual developmental disorder 60 with seizuresSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032823

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder 60 with seizuresMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032823

Submitter: Broad Center for Mendelian Genomics

intellectual developmental disorder 60 with seizuresSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032823

Submitter: PanelApp Australia

intellectual developmental disorder 60 with seizuresSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032823

Submitter: G2P

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 60, with seizuresAD

Manifestation: Neurologic

Intervention: General

Rationale: 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

Refs: 31104773

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AP2M1 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 276

not specifiedTotal: 34

Inborn genetic diseasesTotal: 19

Intellectual developmental disorder 60 with seizuresTotal: 14

AP2M1-related disorderTotal: 9

See casesTotal: 2

Neurodevelopmental disorderTotal: 1

Complex neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004068.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	83 clinvar	3 clinvar	88
missense	1 clinvar	1 clinvar	90 clinvar	6 clinvar	2 clinvar	100
nonsense			4 clinvar			4
start loss						0
frameshift			3 clinvar			3
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	1	1	105	89	5	201

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 62 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004068.4	RefSeq	NP_004059.2	11	MANE Select
ENST00000292807.9	Ensembl	ENSP00000292807.5	11	MANE Select
NM_001025205.2	RefSeq	NP_001020376.1	10	Standard
NM_001311198.2	RefSeq	NP_001298127.1	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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

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

Molecular Function

signal sequence binding
transporter activity
protein binding
lipid binding
clathrin adaptor activity

Cellular Component

lysosomal membrane
cytosol
plasma membrane
AP-2 adaptor complex
endocytic vesicle membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000292807
Coding exons: 11
Length: 9403
Individuals with no LoFs: 124794
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 124796
p: 0.00000801

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.88	46	273	0.169	0.0000173	2890
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000090	0.0000088	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

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}.;

Recessive Scores

pRec: 0.247

Intolerance Scores

LoFtool: 0.206
RVIS EVS: -0.14
RVIS percentile EVS: 42.88

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.945

Gene Damage Prediction

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