AP3B1

Chr 5AR

adaptor related protein complex 3 subunit beta 1

Also known as: ADTB3, ADTB3A, HPS, HPS2, PE

NCBI Gene: 8546 ENSG00000132842 UniProt: O00203 OMIM: 603401

The AP3B1 protein is a subunit of the adaptor protein complex 3 (AP-3) that sorts transmembrane proteins to lysosomes and lysosome-related organelles including melanosomes and platelet dense granules. Mutations cause Hermansky-Pudlak syndrome type 2, an autosomal recessive disorder characterized by oculocutaneous albinism, bleeding diathesis due to platelet storage pool deficiency, and variable pulmonary fibrosis. The gene shows significant constraint against loss-of-function variants (LOEUF 0.344), reflecting its essential cellular function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Hermansky-Pudlak syndrome 2MIM #608233

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Hermansky-Pudlak syndrome 2 · AR · ClinGen 2020

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.34

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — AP3B1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.34LOEUF

pLI 0.615

Z-score 5.63

OE 0.22 (0.14–0.34)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

0.89Z-score

OE missense 0.89 (0.83–0.96)

508 obs / 567.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.22 (0.14–0.34)

0≤0.351.4

Missense OE?0.89 (0.83–0.96)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 13 / 60.1Missense obs/exp: 508 / 567.7Syn Z: 1.37

Background carrier burden — how many people carry a rare variant somewhere in AP3B1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 56

1,207 rare PASS variants

Rare truncating (LoF)

1 in 1,900

134 rare PASS variants

Rare synonymous (reference)

1 in 130

420 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for AP3B1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 95	1 in 1,800
South Asian	~43k	1 in 53	1 in 3,300
Remaining (unassigned)	~30k	1 in 47	1 in 5,000
European (Finnish)	~27k	1 in 330	1 in 1,200
Admixed American	~22k	1 in 48	1 in 1,300
African / African American	~21k	1 in 50	1 in 2,300
East Asian	~20k	1 in 58	1 in 3,300
Ashkenazi Jewish	~13k	1 in 360	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 44	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 24 of 27 coding exons well covered in gnomAD exomes; exons 2, 6, 21 marginal. Genomes: all 27.? see exons ↓