AP3B1

protein-coding

adaptor related protein complex 3 subunit beta 1, the group of Clathrin/coatomer adaptor, adaptin-like, N-terminal domain containing|Adaptor related protein complex 3

Gene summary

This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. The encoded protein is part of the heterotetrameric AP-3 protein complex which interacts with the scaffolding protein clathrin. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 2. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2012]

MANE transcript

NM_003664.5

Inheritance

ClinVar variants

P:80U:431B:218

Top phenotype

Hermansky-Pudlak syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.22

Max pathogenic AF

—

Genomic locus

chr5:77,991,640-78,294,762

External References & Databases

Ensembl (ENSG00000132842)

Transcript & Mutation Effects

hg38 • Region Span ~303.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Hermansky-Pudlak syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011997

Submitter: Labcorp Genetics (formerly Invitae)

Hermansky-Pudlak syndrome 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011997

Submitter: G2P

Hermansky-Pudlak syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011997

Submitter: PanelApp Australia

Hermansky-Pudlak syndrome 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011997

Submitter: ClinGen

*AP3B1* was first reported in relation to autosomal recessive Hermansky-Pudlak syndrome 2 in 1999 (Dell'Angelica et al., PMID 10024875). Hermansky-Pudlak syndrome 2 is a subtype of HPS, characterized by neutropenia and immune defects, in addition to oculocutaneous albinism and bleeding tendency. In some individuals, pulmonary fibrosis and granulomatous colitis are also observed. *AP3B1* encodes the β1 subunit of adaptor complex-3, AP3, which is a coat protein complex that forms intracellular vesicles (Huizing et al., Hermansky-Pudlak Syndrome, GeneReviews). This complex is expressed ubiquitously. In the neurological tissues, however, the β2 subunit encoded by AP3B2 replaces β1 in the AP3 complex. At least 28 nonsense, frameshift and missense variants have been reported in humans (PMID: 28585318). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data: 12 POINTS Variants in this gene have been reported in at least 9 probands in 8 publications (PMIDs 28585318, 16537806, 19679886, 23215637, 10024875, 14566336, 16551969, 11809908) Variants in this gene segregated with disease in 3 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is homozygous loss of function (Huizing et al., Hermansky-Pudlak Syndrome, GeneReviews). Summary of Experimental Data: 4 POINTS This gene-disease association is supported by animal models and in vitro functional assays. The ‘Pearl’ mouse model is a spontaneously mutated mouse that expresses the HPS2 phenotype (PMID: 9931340). Yang et al., generated homozygous *AP3B1* knock-out mice that showed similar phenotypes as that seen in HPS2 patients (PMID: 11058094). In-vitro studies in patient-derived cells and transfected cultures show defective intracellular protein trafficking in *AP3B1* mutants (PMIDs 30630984, 11452004, 14566336, 10024875). In summary, *AP3B1* is definitively associated with autosomal recessive Hermansky-Pudlak syndrome 2. 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 Hemostasis/Thrombosis gene curation expert panel on 2/26/20 (SOP Version 6). Note from Primary Immune Regulatory Disorders GCEP added 01/05/2026: *AP3B1*-related HPS-2 demonstrates immune dysregulation and susceptibility to recurrent infections due to impaired cytotoxic function of NK and T cells, in addition to neutropenia (PMID: 16507770, 32869296, 19679886). Hemophagocytic lymphohistiocytosis (HLH) has been reported in 32 patients in the literature, with at least one patient developing lethal HLH (PMID: 30974211, 36614895). This pattern of immune dysregulation is also reported in other genes associated with lymphocyte cytotoxicity or defects in inflammasome activation, and thus HPS-2 can be listed along with other diseases, such as Griscelli syndrome type 2 and Chediak-Higashi syndrome (PMID: 33641308, 32869296). Additional clinical manifestations, such as severe periodontitis, further illustrate the immune dysfunction in HPS-2 (PMID: 35928686).

Clinical Genomic Database (CGD)

Hermansky-Pudlak syndrome 2AR

Manifestation: Allergy/Immunology/Infectious; Dental; Dermatologic; Hematologic; Neurologic; Ophthalmologic; Pulmonary

Intervention: Allergy/Immunology/Infectious; Dermatologic; Hematologic; Pulmonary

Rationale: Prevention and treatment of bleeding episodes (eg, with DDAVP or platelet/RBC transfusions) can be effective, and aspirin-containing products should be avoided; Skin surveillance and protection can be beneficial; Prompt treatment of pulmonary infections (as well as avoidance of cigarette smoke) to maximize pulmonary function is indicated, including influenza and pneumococcus vaccination

Refs: 10024875; 11809908; 16507770; 16537806; 20301464; 23215637

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AP3B1 variants in ClinVar

12 Conditions Cataloged

Hermansky-Pudlak syndrome 2Total: 813

not specifiedTotal: 132

not providedTotal: 127

Inborn genetic diseasesTotal: 121

AP3B1-related disorderTotal: 37

Autoinflammatory syndromeTotal: 36

Hermansky-Pudlak syndromeTotal: 3

ThrombocytopeniaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003664.5. 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			7 clinvar	197 clinvar		204
missense	2 clinvar	1 clinvar	412 clinvar	18 clinvar	3 clinvar	436
nonsense	12 clinvar	6 clinvar	1 clinvar			19
start loss						0
frameshift	21 clinvar	17 clinvar	2 clinvar			40
splice donor/acceptor (+/-2bp)	4 clinvar	17 clinvar	9 clinvar			30
Total	39	41	431	215	3	729

Highest pathogenic variant AF is 0.000018474726

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 49 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003664.5	RefSeq	NP_003655.3	27	MANE Select
ENST00000255194.11	Ensembl	ENSP00000255194.7	27	MANE Select
NM_001271769.2	RefSeq	NP_001258698.1	26	Standard
NM_001410752.1	RefSeq	NP_001397681.1	23	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysosome - Homo sapiens (human)
miR-targeted genes in lymphocytes - TarBase
miR-targeted genes in muscle cell - TarBase
Golgi Associated Vesicle Biogenesis
Clathrin derived vesicle budding

Biological Process

protein targeting to lysosome
intracellular protein transport
blood coagulation
anterograde axonal transport
synaptic vesicle budding from endosome

Molecular Function

protein phosphatase binding
GTP-dependent protein binding

Cellular Component

lysosomal membrane
Golgi apparatus
membrane
AP-3 adaptor complex
clathrin adaptor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000255194
Coding exons: 27
Length: 294231
Individuals with no LoFs: 125715
Homozygous LoFs: 0
Heterozygous LoFs: 33
Defined: 125748
p: 0.000131

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.890	508	568	0.895	0.0000277	7198
Missense (PolyPhen)		81	122.78	0.65969		1523
Synonymous	1.37	172	197	0.875	0.00000975	2073
Loss of Function	5.63	13	60.1	0.216	0.00000312	742

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.00018	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00013	0.00013	rare
South Asian	0.00023	0.00016	rare
Other	0.00016	0.00016	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: Hermansky-Pudlak syndrome 2 (HPS2) [MIM:608233]: A form of Hermansky-Pudlak syndrome, a genetically heterogeneous autosomal recessive disorder characterized by oculocutaneous albinism, bleeding due to platelet storage pool deficiency, and lysosomal storage defects. This syndrome results from defects of diverse cytoplasmic organelles including melanosomes, platelet dense granules and lysosomes. Ceroid storage in the lungs is associated with pulmonary fibrosis, a common cause of premature death in individuals with HPS. HPS2 differs from the other forms of HPS in that it includes immunodeficiency in its phenotype and patients with HPS2 have an increased susceptibility to infections. {ECO:0000269|PubMed:10024875}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.316

Intolerance Scores

LoFtool: 0.483
RVIS EVS: 0.43
RVIS percentile EVS: 77.29

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.824

Gene Damage Prediction

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