AP1B1

protein-coding

adaptor related protein complex 1 subunit beta 1, the group of Small nucleolar RNA protein coding host genes|Clathrin/coatomer adaptor, adaptin-like, N-terminal domain containing|Adaptor related protein complex 1|MicroRNA protein coding host genes

Gene summary

Adaptor protein complex 1 is found at the cytoplasmic face of coated vesicles located at the Golgi complex, where it mediates both the recruitment of clathrin to the membrane and the recognition of sorting signals within the cytosolic tails of transmembrane receptors. This complex is a heterotetramer composed of two large, one medium, and one small adaptin subunit. The protein encoded by this gene serves as one of the large subunits of this complex and is a member of the adaptin protein family. This gene is a candidate meningioma gene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

Previous symbols:

ADTB1
CLAPB2

MANE transcript

NM_001127.4

Inheritance

ClinVar variants

P:12U:123B:28

Top phenotype

Keratitis-ichthyosis-deafness syndrome, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chr22:29,327,680-29,388,583

External References & Databases

Ensembl (ENSG00000100280)

Transcript & Mutation Effects

hg38 • Region Span ~60.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ichthyosiform erythroderma, corneal involvement, and hearing lossDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009440

Submitter: ClinGen

The *AP1B*1 gene was first reported in relation to autosomal recessive Keratitis-ichthyosis-deafness syndrome in 2019 (Alsaif, H S et al., PMID: 31630791). It is characterized by syndromic early-onset ichthyosis, alopecia, severe sensorineural hearing loss, as well as failure to thrive, mild developmental delay, and later-onset palmoplantar keratoderma. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern and phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, Autosomal Recessive Keratitis-ichthyosis-deafness Syndrome (KIDAR MIM #242150). Eleven variants (including missense, nonsense, frameshift, and large deletions involving exons 1-2 of the gene) have been reported in 10 probands in 7 publications (PMIDs: 31630791, 31630788, 33452671, 33349978, 35144013, 37657632, 32969855) and are included in this curation. 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 functional characterization of fibroblasts derived from affected individuals and from animal models (zebrafish), which show abnormal ATP7A trafficking and auditory defects paralleling the hearing loss in our human subjects with AP1B1 mutations (PMIDs: 31630791, 23593334). In summary, there is definitive evidence supporting the relationship between AP1B1 and autosomal recessive Keratitis-ichthyosis-deafness syndrome. This has been repeatedly demonstrated in both research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen IEM GCEP on the meeting date August, 9, 2024. (SOP Version 10).

ichthyosiform erythroderma, corneal involvement, and hearing lossMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009440

Submitter: Ambry Genetics

ichthyosiform erythroderma, corneal involvement, and hearing lossSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009440

Submitter: PanelApp Australia

ichthyosiform erythroderma, corneal involvement, and hearing lossMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009440

Submitter: G2P

MEDNIK syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012251

Submitter: Orphanet

Clinical Genomic Database (CGD)

Keratitis-ichthyosis-deafness syndrome, autosomal recessiveAR

Manifestation: Audiologic/Otolaryngologic; Dermatologic

Intervention: Audiologic/Otolaryngologic

Rationale: The condition may include hearing loss, recognition and interventions related to speech and language development may be beneficial

Refs: 31630788; 31630791

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AP1B1 variants in ClinVar

5 Conditions Cataloged

Inborn genetic diseasesTotal: 101

AP1B1-related disorderTotal: 31

not providedTotal: 19

Autosomal recessive keratitis-ichthyosis-deafness syndromeTotal: 13

not specifiedTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001127.4. 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			3 clinvar	19 clinvar	1 clinvar	23
missense	2 clinvar		108 clinvar	8 clinvar		118
nonsense	4 clinvar		3 clinvar			7
start loss		1 clinvar				1
frameshift	3 clinvar	1 clinvar				4
splice donor/acceptor (+/-2bp)	1 clinvar		9 clinvar			10
Total	10	2	123	27	1	163

Highest pathogenic variant AF is 0.0000065695253

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 61 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001127.4	RefSeq	NP_001118.3	22	MANE Select
ENST00000357586.7	Ensembl	ENSP00000350199.2	22	MANE Select
NM_001166019.2	RefSeq	NP_001159491.1	20	Standard
NM_001378562.1	RefSeq	NP_001365491.1	21	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
ap1b1	Danio rerio	Structure: neuromast hair cell Quality: functionality abnormal

Gene / Model

Organism

Observed Phenotype

ap1b1

Danio rerio

Structure: neuromast hair cell

Quality: functionality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysosome - Homo sapiens (human)
Golgi Associated Vesicle Biogenesis
Lysosome Vesicle Biogenesis
Clathrin derived vesicle budding
Disease

Biological Process

intracellular protein transport
determination of left/right symmetry
heart development
vesicle-mediated transport
antigen processing and presentation of exogenous peptide antigen via MHC class II

Molecular Function

transporter activity
protein binding
protein kinase binding
clathrin binding

Cellular Component

Golgi membrane
lysosomal membrane
Golgi apparatus
cytosol
clathrin adaptor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000357586
Coding exons: 22
Length: 95500
Individuals with no LoFs: 125730
Homozygous LoFs: 0
Heterozygous LoFs: 18
Defined: 125748
p: 0.0000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.12	376	589	0.638	0.0000362	6188
Missense (PolyPhen)		81	173.78	0.4661		1851
Synonymous	-0.599	270	258	1.05	0.0000177	1909
Loss of Function	5.39	6	45.0	0.133	0.00000208	528

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.000080	0.000079	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Subunit of clathrin-associated adaptor protein complex 1 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.;

Recessive Scores

pRec: 0.225

Intolerance Scores

LoFtool: 0.435
RVIS EVS: -1.53
RVIS percentile EVS: 3.41

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.799

Gene Damage Prediction

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