AP3B2

protein-coding

adaptor related protein complex 3 subunit beta 2, the group of Clathrin/coatomer adaptor, adaptin-like, N-terminal domain containing|Adaptor related protein complex 3

Gene summary

Adaptor protein complex 3 (AP-3 complex) is a heterotrimeric protein complex involved in the formation of clathrin-coated synaptic vesicles. The protein encoded by this gene represents the beta subunit of the neuron-specific AP-3 complex and was first identified as the target antigen in human paraneoplastic neurologic disorders. The encoded subunit binds clathrin and is phosphorylated by a casein kinase-like protein, which mediates synaptic vesicle coat assembly. Defects in this gene are a cause of early-onset epileptic encephalopathy. [provided by RefSeq, Feb 2017]

MANE transcript

NM_001278512.2

Inheritance

AR, AD

ClinVar variants

P:55U:338B:299

Top phenotype

Developmental and epileptic encephalopathy 48

gnomAD constraint

pLI —, LoF o/e 0.21

Max pathogenic AF

—

Genomic locus

chr15:82,659,281-82,710,112

External References & Databases

Ensembl (ENSG00000103723)

Transcript & Mutation Effects

hg38 • Region Span ~50.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental and epileptic encephalopathy, 48STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0015000

Submitter: G2P

undetermined early-onset epileptic encephalopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018614

Submitter: Orphanet

developmental and epileptic encephalopathy, 48STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0015000

Submitter: Labcorp Genetics (formerly Invitae)

developmental and epileptic encephalopathy, 48STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0015000

Submitter: PanelApp Australia

genetic developmental and epileptic encephalopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100062

Submitter: ClinGen

*AP3B2* was first reported in relation to autosomal recessive developmental and epileptic encephalopathy in 2016 (Assoum, et.al. PMID: 27889060). This condition is characterized by early-onset seizures, global developmental delays, hypotonia, microcephaly, visual impairment, motor delays, and abnormal MRI. Fourteen total variants (6 frameshift variants, 4 nonsense variants, 2 canonical splice site variants, 1 silent variant, and 1 large deletion) that have been reported in fourteen probands in five publications (PMIDs: 27889060, 27431290, 36356440, 36493596, 34540776) are included in this curation. RNA studies indicated that a canonical splice site variant and a silent variant led to aberrant transcripts that would lead to a non-functional protein (PMID: 27889060). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by a null mouse model that recapitulates the human phenotype by displaying behavioral abnormalities and seizures (PMID: 15537701; more detailed information can be found at (https://www.informatics.jax.org/reference/J:205908)). In summary, there is definitive evidence supporting the relationship between *AP3B2* and autosomal recessive developmental and epileptic encephalopathy. 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 September 16, 2025 (SOP Version 11).

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 48AR

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: 27431290; 27431290

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AP3B2 variants in ClinVar

18 Conditions Cataloged

not providedTotal: 837

Inborn genetic diseasesTotal: 137

not specifiedTotal: 64

Developmental and epileptic encephalopathy, 48Total: 52

AP3B2-related disorderTotal: 41

Epileptic encephalopathyTotal: 2

MicrocephalyTotal: 2

Generalized hypotoniaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001278512.2. 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		1 clinvar	3 clinvar	282 clinvar	3 clinvar	289
missense			326 clinvar	13 clinvar	1 clinvar	340
nonsense	12 clinvar	6 clinvar	1 clinvar			19
start loss			1 clinvar			1
frameshift	16 clinvar	9 clinvar	1 clinvar			26
splice donor/acceptor (+/-2bp)	1 clinvar	10 clinvar	6 clinvar			17
Total	29	26	338	295	4	692

Highest pathogenic variant AF is 0.000013141641

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 36 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001278512.2	RefSeq	NP_001265441.1	27	MANE Select
ENST00000535359.6	Ensembl	ENSP00000440984.1	27	MANE Select
NM_001278511.2	RefSeq	NP_001265440.1	25	Standard
NM_001348440.2	RefSeq	NP_001335369.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysosome - Homo sapiens (human)

Biological Process

intracellular protein transport
post-Golgi vesicle-mediated transport
anterograde axonal transport
anterograde synaptic vesicle transport

Molecular Function

transporter activity

Cellular Component

Golgi apparatus
AP-3 adaptor complex
COPI-coated vesicle
clathrin-coated vesicle membrane
axon cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261722
Coding exons: 26
Length: 50634
Individuals with no LoFs: 124621
Homozygous LoFs: 0
Heterozygous LoFs: 29
Defined: 124650
p: 0.000116

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.92	413	617	0.669	0.0000342	6997
Missense (PolyPhen)		57	143.83	0.3963		1533
Synonymous	-0.146	253	250	1.01	0.0000142	2174
Loss of Function	5.37	11	53.3	0.206	0.00000262	631

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00026	0.00026	rare
Latino/Admixed American	0.00021	0.00020	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000093	0.000093	rare
European (Non-Finnish)	0.00012	0.00012	rare
South Asian	0.000065	0.000065	rare
Other	0.00017	0.00017	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Subunit of non-clathrin- and clathrin-associated adaptor protein complex 3 (AP-3) that plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes. The AP complexes mediate both the recruitment of clathrin to membranes and the recognition of sorting signals within the cytosolic tails of transmembrane cargo molecules. AP-3 appears to be involved in the sorting of a subset of transmembrane proteins targeted to lysosomes and lysosome-related organelles. In concert with the BLOC-1 complex, AP-3 is required to target cargos into vesicles assembled at cell bodies for delivery into neurites and nerve terminals.;
Disease: DISEASE: Epileptic encephalopathy, early infantile, 48 (EIEE48) [MIM:617276]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE48 is an autosomal recessive form characterized by onset of seizures in the first year of life. Affected individuals manifest global developmental delay, intellectual disability, absent speech, and poor, if any, motor development. {ECO:0000269|PubMed:27431290, ECO:0000269|PubMed:27889060}. Note=The disease may be caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.194

Intolerance Scores

RVIS EVS: -1.62
RVIS percentile EVS: 2.93

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.929

Gene Damage Prediction

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