AP1B1

Summary

AP1B1 (adaptor related protein complex 1 subunit beta 1, HGNC:554) is a protein-coding gene on chromosome 22q12.2, encoding AP-1 complex subunit beta-1 (Q10567). 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.

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.

Source: NCBI Gene 162 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ichthyosiform erythroderma, corneal involvement, and hearing loss (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 15
• Clinical variants (ClinVar): 200 total — 25 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 30
• Druggable target: yes
• MANE Select transcript: NM_001127

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:554
Approved symbol	AP1B1
Name	adaptor related protein complex 1 subunit beta 1
Location	22q12.2
Locus type	gene with protein product
Status	Approved
Aliases	BAM22, AP105A
Ensembl gene	ENSG00000100280
Ensembl biotype	protein_coding
OMIM	600157
Entrez	162

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 26 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000317368, ENST00000357586, ENST00000405198, ENST00000415756, ENST00000421126, ENST00000432560, ENST00000472057, ENST00000473606, ENST00000482818, ENST00000852342, ENST00000852343, ENST00000852344, ENST00000852345, ENST00000852346, ENST00000852347, ENST00000852348, ENST00000852349, ENST00000852350, ENST00000852351, ENST00000921603, ENST00000921604, ENST00000921605, ENST00000921606, ENST00000921607, ENST00000921608, ENST00000921609, ENST00000921610, ENST00000921611, ENST00000952519

RefSeq mRNA: 8 — MANE Select: NM_001127 NM_001127, NM_001166019, NM_001378562, NM_001378563, NM_001378564, NM_001378565, NM_001378566, NM_145730

CCDS: CCDS13855, CCDS13856, CCDS54515

Canonical transcript exons

ENST00000357586 — 23 exons

Exon	Start	End
ENSE00001276406	29330378	29330532
ENSE00001555387	29327680	29328895
ENSE00001620893	29341501	29341760
ENSE00001630121	29342285	29342383
ENSE00001647124	29351171	29351266
ENSE00001667388	29340656	29340857
ENSE00001673404	29358726	29358971
ENSE00001675596	29356426	29356616
ENSE00001707118	29351705	29351825
ENSE00001713547	29354650	29354871
ENSE00001727217	29350035	29350150
ENSE00001754518	29339754	29339774
ENSE00001759805	29329712	29329720
ENSE00001761358	29349218	29349383
ENSE00001795295	29359824	29359959
ENSE00002296219	29367207	29367270
ENSE00003465248	29334265	29334410
ENSE00003496783	29338990	29339133
ENSE00003601455	29363001	29363106
ENSE00003642356	29331449	29331533
ENSE00003649781	29331787	29331916
ENSE00003679401	29330623	29330709
ENSE00003912913	29388424	29388570

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 97.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 79.1377 / max 600.9025, expressed in 1826 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193522	73.7238	1826
193521	3.6476	1483
193523	1.7555	1066
209443	0.0108	4

Top tissues by expression

291 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
endometrium epithelium	UBERON:0004811	97.22	gold quality
middle frontal gyrus	UBERON:0002702	96.35	gold quality
paraflocculus	UBERON:0005351	95.76	gold quality
Brodmann (1909) area 10	UBERON:0013541	95.32	gold quality
frontal pole	UBERON:0002795	95.25	gold quality
mucosa of transverse colon	UBERON:0004991	94.79	gold quality
right adrenal gland cortex	UBERON:0035827	94.61	gold quality
spleen	UBERON:0002106	94.52	gold quality
lymph node	UBERON:0000029	94.46	gold quality
left adrenal gland	UBERON:0001234	94.40	gold quality
right adrenal gland	UBERON:0001233	94.36	gold quality
esophagus mucosa	UBERON:0002469	94.34	gold quality
granulocyte	CL:0000094	94.25	gold quality
left adrenal gland cortex	UBERON:0035825	94.25	gold quality
right frontal lobe	UBERON:0002810	94.10	gold quality
adrenal cortex	UBERON:0001235	93.93	gold quality
small intestine Peyer’s patch	UBERON:0003454	93.76	gold quality
skin of leg	UBERON:0001511	93.65	gold quality
lower esophagus mucosa	UBERON:0035834	93.53	gold quality
adrenal gland	UBERON:0002369	93.52	gold quality
cingulate cortex	UBERON:0003027	93.50	gold quality
anterior cingulate cortex	UBERON:0009835	93.47	gold quality
monocyte	CL:0000576	93.40	gold quality
body of stomach	UBERON:0001161	93.24	gold quality
adenohypophysis	UBERON:0002196	93.24	gold quality
leukocyte	CL:0000738	93.10	gold quality
mononuclear cell	CL:0000842	93.04	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.00	gold quality
skin of abdomen	UBERON:0001416	92.97	gold quality
prefrontal cortex	UBERON:0000451	92.93	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	40.26
E-ANND-3	yes	15.17
E-CURD-11	no	45.02

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

48 targeting AP1B1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-4502	99.65	66.99	1021
HSA-MIR-378A-5P	99.65	66.33	1311
HSA-MIR-3682-3P	99.58	67.63	865
HSA-MIR-12123	99.52	71.79	2990

Literature-anchored findings (GeneRIF, showing 8)

• The conclude that in addition to its role in endocytosis, ARH cooperates with AP-1B in basolateral exocytosis of LDLR from recycling endosomes. (PMID:21444685)
• A protein encoded by this locus was found to be differentially expressed in postmortem brains from patients with atypical frontotemporal lobar degeneration. (PMID:22360420)
• AP1B regulates basolateral EGFR membrane delivery predominantly in the biosynthetic route in MDCK cells monolayers. (PMID:23205726)
• both ubiquitous (AP-1A) and epithelium-specific (AP-1B) forms of the tetrameric clathrin adaptor AP-1 are capable of carrying out basolateral sorting of ClC-2. (PMID:25739457)
• Transduction of affected cells with wild-type AP1B1 rescues the vesicular phenotype. (PMID:31630788)
• Three individuals from two unrelated families in whom a MEDNIK-like phenotype segregates with two homozygous null variants in AP1B1. (PMID:31630791)
• Novel function for AP-1B during cell migration. (PMID:32816642)
• MEDNIK-like syndrome due to compound heterozygous mutations in AP1B1. (PMID:33349978)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ap1b1	ENSDARG00000020621
mus_musculus	Ap1b1	ENSMUSG00000009090
rattus_norvegicus	Ap1b1	ENSRNOG00000008786
drosophila_melanogaster	AP-1-2beta	FBGN0010380
caenorhabditis_elegans		WBGENE00000160

Paralogs (4): AP2B1 (ENSG00000006125), AP3B2 (ENSG00000103723), AP3B1 (ENSG00000132842), AP4B1 (ENSG00000134262)

Protein

Protein identifiers

AP-1 complex subunit beta-1 — Q10567 (reviewed: Q10567)

Alternative names: Adaptor protein complex AP-1 subunit beta-1, Adaptor-related protein complex 1 subunit beta-1, Beta-1-adaptin, Beta-adaptin 1, Clathrin assembly protein complex 1 beta large chain, Golgi adaptor HA1/AP1 adaptin beta subunit

All UniProt accessions (3): Q10567, C9J1E7, H7C034

UniProt curated annotations — full annotation on UniProt →

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.

Subunit / interactions. Adaptor protein complex 1 (AP-1) is a heterotetramer composed of two large adaptins (gamma-type subunit AP1G1 and beta-type subunit AP1B1), a medium adaptin (mu-type subunit AP1M1 or AP1M2) and a small adaptin (sigma-type subunit AP1S1 or AP1S2 or AP1S3).

Subcellular location. Golgi apparatus. Cytoplasmic vesicle. Clathrin-coated vesicle membrane.

Tissue specificity. Widely expressed.

Disease relevance. Keratitis-ichthyosis-deafness syndrome, autosomal recessive (KIDAR) [MIM:242150] An autosomal recessive form of keratitis-ichthyosis-deafness syndrome, a disease characterized by the association of hyperkeratotic skin lesions with vascularizing keratitis and profound sensorineural hearing loss. KIDAR patients manifest ichthyosis, failure to thrive and developmental delay in childhood, thrombocytopenia, photophobia, and progressive hearing loss. Low plasma copper and ceruloplasmin levels have been reported in some patients. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the adaptor complexes large subunit family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q10567-1	A	yes
Q10567-2	B
Q10567-3	C
Q10567-4	4

RefSeq proteins (8): NP_001118, NP_001159491, NP_001365491, NP_001365492, NP_001365493, NP_001365494, NP_001365495, NP_663782 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000225	Armadillo	Repeat
IPR002553	Clathrin/coatomer_adapt-like_N	Domain
IPR008152	Clathrin_a/b/g-adaptin_app_Ig	Domain
IPR009028	Coatomer/calthrin_app_sub_C	Homologous_superfamily
IPR011989	ARM-like	Homologous_superfamily
IPR012295	TBP_dom_sf	Homologous_superfamily
IPR013037	Clathrin_b-adaptin_app_Ig-like	Homologous_superfamily
IPR013041	Clathrin_app_Ig-like_sf	Homologous_superfamily
IPR015151	B-adaptin_app_sub_C	Domain
IPR016024	ARM-type_fold	Homologous_superfamily
IPR016342	AP_complex_bsu_1_2_4	Family
IPR026739	AP_beta	Family

Pfam: PF01602, PF02883, PF09066

UniProt features (62 total): helix 38, strand 7, turn 6, sequence variant 3, splice variant 3, modified residue 2, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

20 structures.

PDB	Method	Resolution (Å)
7R4H	ELECTRON MICROSCOPY	2.34
4P6Z	X-RAY DIFFRACTION	3
6CM9	ELECTRON MICROSCOPY	3.73
6DFF	ELECTRON MICROSCOPY	3.9
6D83	ELECTRON MICROSCOPY	4.27
6D84	ELECTRON MICROSCOPY	6.72
6CRI	ELECTRON MICROSCOPY	6.8
4HMY	X-RAY DIFFRACTION	7
8D4E	ELECTRON MICROSCOPY	9.2
8D4C	ELECTRON MICROSCOPY	9.3
8D9W	ELECTRON MICROSCOPY	9.3
8D9V	ELECTRON MICROSCOPY	9.4
7UX3	ELECTRON MICROSCOPY	9.6
8D4D	ELECTRON MICROSCOPY	9.6
8D4F	ELECTRON MICROSCOPY	9.8
8D4G	ELECTRON MICROSCOPY	11.6
8D9R	ELECTRON MICROSCOPY	20
8D9S	ELECTRON MICROSCOPY	20
8D9T	ELECTRON MICROSCOPY	20
8D9U	ELECTRON MICROSCOPY	20

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q10567-F1	82.46	0.57

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 318, 574

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-164940	Nef mediated downregulation of MHC class I complex cell surface expression
R-HSA-2132295	MHC class II antigen presentation
R-HSA-432720	Lysosome Vesicle Biogenesis
R-HSA-432722	Golgi Associated Vesicle Biogenesis
R-HSA-1280218	Adaptive Immune System
R-HSA-162906	HIV Infection
R-HSA-162909	Host Interactions of HIV factors
R-HSA-1643685	Disease
R-HSA-164938	Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters
R-HSA-164952	The role of Nef in HIV-1 replication and disease pathogenesis
R-HSA-168256	Immune System
R-HSA-199991	Membrane Trafficking
R-HSA-199992	trans-Golgi Network Vesicle Budding
R-HSA-5653656	Vesicle-mediated transport
R-HSA-5663205	Infectious disease
R-HSA-9824446	Viral Infection Pathways

MSigDB gene sets: 305 (showing top): GRUETZMANN_PANCREATIC_CANCER_DN, PAX4_01, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOCC_VACUOLAR_MEMBRANE, GOBP_VESICLE_ORGANIZATION, MORF_HDAC1, GOBP_CELLULAR_PIGMENTATION, KEGG_LYSOSOME, REACTOME_THE_ROLE_OF_NEF_IN_HIV_1_REPLICATION_AND_DISEASE_PATHOGENESIS, TGACCTY_ERR1_Q2, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, COUP_01, GOBP_PIGMENTATION

GO Biological Process (9): kidney development (GO:0001822), intracellular protein transport (GO:0006886), determination of left/right symmetry (GO:0007368), heart development (GO:0007507), vesicle-mediated transport (GO:0016192), platelet dense granule organization (GO:0060155), basolateral protein secretion (GO:0110010), melanosome assembly (GO:1903232), protein transport (GO:0015031)

GO Molecular Function (3): protein kinase binding (GO:0019901), clathrin binding (GO:0030276), protein binding (GO:0005515)

GO Cellular Component (16): Golgi membrane (GO:0000139), lysosomal membrane (GO:0005765), early endosome (GO:0005769), Golgi apparatus (GO:0005794), cytosol (GO:0005829), synaptic vesicle (GO:0008021), AP-1 adaptor complex (GO:0030121), cytoplasmic vesicle membrane (GO:0030659), trans-Golgi network membrane (GO:0032588), cytoplasm (GO:0005737), endomembrane system (GO:0012505), membrane (GO:0016020), membrane coat (GO:0030117), clathrin adaptor complex (GO:0030131), clathrin-coated vesicle membrane (GO:0030665), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
trans-Golgi Network Vesicle Budding	2
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	1
Adaptive Immune System	1
Immune System	1
Viral Infection Pathways	1
HIV Infection	1
The role of Nef in HIV-1 replication and disease pathogenesis	1
Host Interactions of HIV factors	1
Vesicle-mediated transport	1
Membrane Trafficking	1
Disease	1
Infectious disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	4
cellular anatomical structure	4
animal organ development	2
intracellular protein localization	2
transport	2
renal system development	1
protein transport	1
intracellular transport	1
determination of bilateral symmetry	1
left/right pattern formation	1
circulatory system development	1
cellular process	1
secretory granule organization	1
protein secretion	1
melanosome organization	1
organelle assembly	1
establishment of protein localization	1
kinase binding	1
protein binding	1
binding	1
Golgi apparatus	1
bounding membrane of organelle	1
lysosome	1
lytic vacuole membrane	1
endosome	1
endomembrane system	1
intracellular membrane-bounded organelle	1
exocytic vesicle	1
presynapse	1
clathrin coat of trans-Golgi network vesicle	1
clathrin adaptor complex	1
vesicle membrane	1
cytoplasmic vesicle	1
trans-Golgi network	1
organelle membrane	1
intracellular anatomical structure	1
vacuole	1
plasma membrane	1
coated membrane	1
membrane protein complex	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

160 interactions, top by confidence:

A	B	Type	Score
SNX9	SYNJ1	psi-mi:“MI:0914”(association)	0.790
EGFR	CTNND1	psi-mi:“MI:0914”(association)	0.750
AMPH	BIN1	psi-mi:“MI:0914”(association)	0.740
AP1B1	Ap1g1	psi-mi:“MI:0915”(physical association)	0.740
Ap1m1	AP1B1	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
AP1S2	AP1G1	psi-mi:“MI:0914”(association)	0.660
Ap1g1	Ap1m1	psi-mi:“MI:0914”(association)	0.660
EGFR	AP1B1	psi-mi:“MI:0915”(physical association)	0.650
GPR156	PLD2	psi-mi:“MI:0914”(association)	0.640
AP2S1	AP2A2	psi-mi:“MI:0914”(association)	0.640
NIPAL1	ESYT2	psi-mi:“MI:0914”(association)	0.640
SLC17A5	LGALS8	psi-mi:“MI:0914”(association)	0.640
CHEK2	PPM1G	psi-mi:“MI:0914”(association)	0.560
AP1B1	nef	psi-mi:“MI:0407”(direct interaction)	0.540
nef	AP1B1	psi-mi:“MI:0915”(physical association)	0.540
MAPT	KIF2A	psi-mi:“MI:0914”(association)	0.530
EGFR	NDUFA4	psi-mi:“MI:0914”(association)	0.530

BioGRID (350): AP1B1 (Affinity Capture-MS), AP1B1 (Affinity Capture-MS), AP1B1 (Affinity Capture-MS), AP1B1 (Affinity Capture-MS), AP1B1 (Affinity Capture-MS), AP1B1 (Affinity Capture-MS), AP1B1 (Affinity Capture-MS), AP1B1 (Affinity Capture-MS), AP1B1 (Co-fractionation), AP1B1 (Co-fractionation), AP1B1 (Co-fractionation), AP1B1 (Co-fractionation), AP1B1 (Co-fractionation), AP1B1 (Co-fractionation), AP1B1 (Co-fractionation)

ESM2 similar proteins: A0A3Q1LSX9, A1A5G0, A1A5K2, A2A5R2, A2APV2, A2VE70, D3ZYR1, O00203, O04376, O35643, O60308, O75122, P52303, Q05397, Q08AM6, Q08DS7, Q0JRZ9, Q10567, Q13367, Q28FH2, Q32PG1, Q3UQN2, Q4U0G1, Q561M0, Q5R807, Q5ZIW5, Q6NUP7, Q6NXC0, Q6NYW6, Q6ZPF4, Q7TSU1, Q7YRF1, Q7Z460, Q80TV8, Q8BRT1, Q8C0Y0, Q8IVF7, Q8LF36, Q8N7B6, Q8RW96

Diamond homologs: O35643, O43005, O43079, O81742, P27351, P36000, P52303, P62944, P63009, P63010, Q08DS7, Q10567, Q13367, Q54X82, Q9DBG3, Q9LDK9, Q9SUS3, Q9WV76, Q9Y6B7, O00203, Q32PG1, Q7YRF1, Q9JME5, Q9Z1T1, Q54R84

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
AP1B1	“form complex”	“AP-1 complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 158 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
WNT5A-dependent internalization of FZD4	8	60.9×	1e-11
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	9	57.1×	9e-13
The role of Nef in HIV-1 replication and disease pathogenesis	9	57.1×	9e-13
VLDLR internalisation and degradation	6	42.8×	1e-07
LDL clearance	7	38.1×	2e-08
Trafficking of GluR2-containing AMPA receptors	5	33.6×	7e-06
Host Interactions of HIV factors	9	30.2×	6e-10
Plasma lipoprotein clearance	6	28.6×	1e-06

GO biological processes:

GO term	Partners	Fold	FDR
clathrin coat assembly	8	56.8×	2e-10
synaptic vesicle endocytosis	13	44.9×	8e-16
clathrin-dependent endocytosis	9	41.8×	2e-10
endocytosis	14	10.7×	1e-08
vesicle-mediated transport	12	9.2×	1e-06
intracellular protein transport	15	7.8×	2e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

200 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	25
Likely pathogenic	2
Uncertain significance	103
Likely benign	19
Benign	24

Top pathogenic / likely-pathogenic (27)

Variant ID	HGVS	Classification
1048800	NM_001127.4(AP1B1):c.1263C>A (p.Tyr421Ter)	Pathogenic
1076222	NC_000022.10:g.(?29083885)(30337586_?)del	Pathogenic
155348	GRCh38/hg38 22q12.1-12.2(chr22:26451042-31451926)x1	Pathogenic
1700245	NM_001127.4(AP1B1):c.322C>T (p.Arg108Trp)	Pathogenic
1700246	NM_001127.4(AP1B1):c.668T>C (p.Leu223Pro)	Pathogenic
1700247	NM_001127.4(AP1B1):c.1852C>T (p.Gln618Ter)	Pathogenic
1700248	NM_001127.4(AP1B1):c.2677C>T (p.Gln893Ter)	Pathogenic
1807757	GRCh37/hg19 22q12.1-12.2(chr22:26614429-29847680)x1	Pathogenic
3062455	GRCh37/hg19 22q12.2(chr22:29765949-29812660)x1	Pathogenic
3247093	NC_000022.10:g.(?29083885)(30090791_?)del	Pathogenic
3247149	NC_000022.10:g.(?29621477)(30035211_?)del	Pathogenic
3346881	NM_001127.4(AP1B1):c.863del (p.Leu288fs)	Pathogenic
4071487	NM_001127.4(AP1B1):c.667del (p.Leu223fs)	Pathogenic
4075887	GRCh37/hg19 22q12.2(chr22:29762157-29817644)x1	Pathogenic
4279343	GRCh37/hg19 22q12.2(chr22:29765950-29818177)x1	Pathogenic
565022	GRCh37/hg19 22q12.2(chr22:29644625-31051719)x1	Pathogenic
57002	GRCh38/hg38 22q12.1-12.3(chr22:26979579-33992220)x3	Pathogenic
59072	GRCh38/hg38 22q12.1-12.2(chr22:26221273-29477543)x1	Pathogenic
59074	GRCh38/hg38 22q12.1-12.2(chr22:28441035-30276511)x1	Pathogenic
59075	GRCh38/hg38 22q12.1-12.2(chr22:28856144-29506277)x1	Pathogenic
805794	NC_000022.10:g.29758984_29815476del	Pathogenic
805795	NM_001127.4(AP1B1):c.38-1G>A	Pathogenic
805796	NM_001127.4(AP1B1):c.430T>C (p.Cys144Arg)	Pathogenic
805797	NM_001127.4(AP1B1):c.2335del (p.Leu779fs)	Pathogenic
805798	NM_001127.4(AP1B1):c.2374G>T (p.Glu792Ter)	Pathogenic
1339533	NM_001127.4(AP1B1):c.2T>C (p.Met1Thr)	Likely pathogenic
442415	GRCh37/hg19 22q12.1-12.3(chr22:28349854-33013062)x3	Likely pathogenic

SpliceAI

4147 predictions. Top by Δscore:

Variant	Effect	Δscore
22:29328893:CAG:C	acceptor_gain	1.0000
22:29329762:C:CT	acceptor_gain	1.0000
22:29330372:TCTCA:T	donor_loss	1.0000
22:29330373:CTCA:C	donor_loss	1.0000
22:29330374:TCA:T	donor_loss	1.0000
22:29330375:CAC:C	donor_loss	1.0000
22:29330376:A:AC	donor_gain	1.0000
22:29330376:A:T	donor_loss	1.0000
22:29330377:C:CC	donor_gain	1.0000
22:29330377:CCGTG:C	donor_gain	1.0000
22:29330528:AGCCT:A	acceptor_gain	1.0000
22:29330529:GCCT:G	acceptor_gain	1.0000
22:29330530:CCTC:C	acceptor_gain	1.0000
22:29330531:CT:C	acceptor_gain	1.0000
22:29330533:C:CA	acceptor_loss	1.0000
22:29330533:C:CC	acceptor_gain	1.0000
22:29330534:T:A	acceptor_loss	1.0000
22:29330542:C:CT	acceptor_gain	1.0000
22:29330617:CCTCA:C	donor_loss	1.0000
22:29330618:CTCA:C	donor_loss	1.0000
22:29330619:TCA:T	donor_loss	1.0000
22:29330620:CAC:C	donor_loss	1.0000
22:29330621:A:AT	donor_loss	1.0000
22:29330705:CCGGT:C	acceptor_gain	1.0000
22:29330706:CGGT:C	acceptor_gain	1.0000
22:29330706:CGGTC:C	acceptor_gain	1.0000
22:29330710:C:CC	acceptor_gain	1.0000
22:29330710:CT:C	acceptor_loss	1.0000
22:29331444:CTCA:C	donor_loss	1.0000
22:29331445:TCA:T	donor_loss	1.0000

AlphaMissense

6235 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:29331529:G:T	A815D	1.000
22:29334267:G:C	N769K	1.000
22:29334267:G:T	N769K	1.000
22:29334379:A:G	L732P	1.000
22:29341579:A:T	V573D	1.000
22:29341609:A:G	L563P	1.000
22:29341675:A:T	V541E	1.000
22:29341687:G:T	A537D	1.000
22:29341706:A:G	S531P	1.000
22:29341708:A:G	L530P	1.000
22:29341708:A:T	L530Q	1.000
22:29341711:A:G	L529P	1.000
22:29341711:A:T	L529Q	1.000
22:29341714:C:G	R528P	1.000
22:29341715:G:T	R528S	1.000
22:29341716:C:A	W527C	1.000
22:29341716:C:G	W527C	1.000
22:29341718:A:G	W527R	1.000
22:29341718:A:T	W527R	1.000
22:29341729:C:T	G523D	1.000
22:29341730:C:G	G523R	1.000
22:29341732:C:G	R522P	1.000
22:29341733:G:T	R522S	1.000
22:29341735:T:A	D521V	1.000
22:29341735:T:G	D521A	1.000
22:29341736:C:G	D521H	1.000
22:29341738:C:G	R520P	1.000
22:29341741:A:G	L519P	1.000
22:29342292:G:T	A510D	1.000
22:29342301:A:G	L507P	1.000

dbSNP variants (sampled 300 via entrez): RS1000023895 (22:29339592 C>T), RS1000030631 (22:29386908 C>G), RS1000098039 (22:29338261 G>A), RS1000115030 (22:29388015 GTTT>G,GTT,GTTTT), RS1000132468 (22:29335222 C>G,T), RS1000185584 (22:29335483 C>T), RS1000216033 (22:29362174 C>T), RS1000244921 (22:29340999 C>A,T), RS1000268417 (22:29361940 C>A), RS1000372487 (22:29366971 CT>C,CTT), RS1000449335 (22:29333866 C>A), RS1000572269 (22:29355844 A>G), RS1000576924 (22:29350423 A>G), RS1000622239 (22:29338263 A>G), RS1000678886 (22:29329192 C>G,T)

Disease associations

OMIM: gene MIM:600157 | disease phenotypes: MIM:242150, MIM:101000

GenCC curated gene-disease

Disease	Classification	Inheritance
ichthyosiform erythroderma, corneal involvement, and hearing loss	Definitive	Autosomal recessive
MEDNIK syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
ichthyosiform erythroderma, corneal involvement, and hearing loss	Definitive	AR

Mondo (3): ichthyosiform erythroderma, corneal involvement, and hearing loss (MONDO:0009440), NF2-related schwannomatosis (MONDO:0007039), MEDNIK syndrome (MONDO:0012251)

Orphanet (2): KID syndrome (Orphanet:477), Full NF2-related schwannomatosis (Orphanet:637)

HPO phenotypes

30 total (30 of 30 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0000509	Conjunctivitis
HP:0000545	Myopia
HP:0000563	Keratoconus
HP:0000613	Photophobia
HP:0000633	Decreased lacrimation
HP:0000962	Hyperkeratosis
HP:0000982	Palmoplantar keratoderma
HP:0001019	Erythroderma
HP:0001249	Intellectual disability
HP:0001263	Global developmental delay
HP:0001394	Cirrhosis
HP:0001406	Intrahepatic cholestasis
HP:0001508	Failure to thrive
HP:0001596	Alopecia
HP:0001808	Fragile nails
HP:0002059	Cerebral atrophy
HP:0002242	Abnormal intestine morphology
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003073	Hypoalbuminemia
HP:0003577	Congenital onset
HP:0004322	Short stature
HP:0008064	Ichthyosis
HP:0008070	Sparse hair
HP:0009830	Peripheral neuropathy
HP:0010837	Decreased circulating ceruloplasmin concentration
HP:0011967	Decreased circulating copper concentration
HP:0012202	Increased serum bile acid concentration
HP:0030948	Elevated gamma-glutamyltransferase level

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST000555_7	Carotid atherosclerosis in HIV infection	2.000000e-06
GCST002553_2	Pancreatic cancer	1.000000e-08
GCST004611_169	High light scatter reticulocyte count	5.000000e-10
GCST004612_190	High light scatter reticulocyte percentage of red cells	2.000000e-10
GCST004628_125	Immature fraction of reticulocytes	1.000000e-11
GCST006288_695	Heel bone mineral density	2.000000e-14
GCST006288_93	Heel bone mineral density	4.000000e-11
GCST006979_196	Heel bone mineral density	2.000000e-19
GCST90002385_576	High light scatter reticulocyte count	4.000000e-25
GCST90002386_531	High light scatter reticulocyte percentage of red cells	5.000000e-25
GCST90002387_176	Immature fraction of reticulocytes	1.000000e-12
GCST90002405_413	Reticulocyte count	4.000000e-18
GCST90002406_566	Reticulocyte fraction of red cells	5.000000e-18
GCST90011899_45	Aspartate aminotransferase levels	5.000000e-15
GCST90014033_77	Haemorrhoidal disease	1.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007986	reticulocyte count
EFO:0009270	heel bone mineral density
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C563739	Erythrokeratodermia Variabilis 3 (supp.)
C537363	Ichthyosiform erythroderma, corneal involvement, deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630824 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.68	Kd	2100	nM	CHEMBL4647346

PubChem BioAssay actives

1 with measured affinity, of 1 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-carboxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-methylpentanoyl]amino]-3-methylbutanoyl]amino]-3-phenylpropanoyl]amino]-4-carboxybutanoyl]amino]-3-carboxypropanoyl]amino]-3-phenylpropanoyl]amino]propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]amino]acetyl]amino]-4-methylsulfanylbutanoyl]amino]hexanoyl]amino]-3-carboxypropanoyl]amino]butanedioic acid	1655993: Binding affinity to beta-adaptin 1 (unknown origin) by fluorescence polarization assay	kd	2.1000	uM

CTD chemical–gene interactions

51 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, affects cotreatment, increases expression	4
bisphenol F	increases expression, affects cotreatment, decreases expression	2
bisphenol A	increases expression	2
aristolochic acid I	increases expression	1
dicrotophos	increases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression	1
beta-lapachone	decreases expression	1
perfluorooctanoic acid	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
aflatoxin B2	decreases methylation	1
methacrylaldehyde	increases abundance, affects cotreatment, increases oxidation	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
eprenetapopt	affects reaction, affects expression	1
bisphenol S	increases expression	1
bis-N,N-dimethylamino-2-(N-methylpyrrolyl)methyl cyclopentadienyl titanium (IV)	decreases expression	1
bisphenol AF	increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Ethanol	increases expression	1
Arsenic	affects methylation	1
Atrazine	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Coumestrol	increases expression, affects cotreatment	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4616366	Binding	Binding affinity to beta-adaptin 1 (unknown origin) by fluorescence polarization assay	HOPPI-NMR: Hot-Peptide-Based Screening Assay for Inhibitors of Protein-Protein Interactions by NMR. — ACS Med Chem Lett

Cellosaurus cell lines

3 cell lines: 2 transformed cell line, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2RR	Abcam HEK293T AP1B1 KO	Transformed cell line	Female
CVCL_D8Z7	Ubigene HEK293 AP1B1 KO	Transformed cell line	Female
CVCL_E0TM	Ubigene Hep G2 AP1B1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

39 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00004437	PHASE2	COMPLETED	Phase II Study of the Multichannel Auditory Brain Stem Implant for Deafness Following Surgery for Neurofibromatosis 2
NCT00911248	PHASE2	TERMINATED	PTC299 for Treatment of Neurofibromatosis Type 2
NCT00973739	PHASE2	COMPLETED	Lapatinib Study for Children and Adults With Neurofibromatosis Type 2 (NF2) and NF2-Related Tumors
NCT01125046	PHASE2	COMPLETED	Bevacizumab in Treating Patients With Recurrent or Progressive Meningiomas
NCT01207687	PHASE2	COMPLETED	Bevacizumab for Symptomatic Vestibular Schwannoma in Neurofibromatosis Type 2 (NF2)
NCT01345136	PHASE2	TERMINATED	Study of RAD001 for Treatment of NF2-related Vestibular Schwannoma
NCT01419639	PHASE2	COMPLETED	Phase II Study of Everolimus (RAD001) in Children and Adults With Neurofibromatosis Type 2
NCT01490476	PHASE2	COMPLETED	Efficacy and Safety Study of RAD001 in the Growth of the Vestibular Schwannoma(s) in Neurofibromatosis 2 (NF2) Patients
NCT01767792	PHASE2	COMPLETED	Phase 2 Study of Bevacizumab in Children and Young Adults With NF 2 and Progressive Vestibular Schwannomas
NCT02104323	PHASE2	COMPLETED	Endostatin Study for Patients With Neurofibromatosis Type 2 (NF2) and NF2-Related Tumors
NCT02129647	PHASE2	COMPLETED	Study of Axitinib in Patients With Neurofibromatosis Type 2 and Progressive Vestibular Schwannomas
NCT02831257	PHASE2	COMPLETED	AZD2014 In NF2 Patients With Progressive or Symptomatic Meningiomas
NCT02934256	PHASE2	COMPLETED	Icotinib Study for Patients With Neurofibromatosis Type 2 (NF2) and NF2-Related Tumors
NCT03079999	PHASE2	ACTIVE_NOT_RECRUITING	Study of Aspirin in Patients With Vestibular Schwannoma
NCT03095248	PHASE2	TERMINATED	Trial of Selumetinib in Patients With Neurofibromatosis Type II Related Tumors
NCT04283669	PHASE2	COMPLETED	Phase 2 Clinical Trial of Crizotinib for Children and Adults With Neurofibromatosis Type 2 and Progressive Vestibular Schwannomas
NCT04374305	PHASE2	RECRUITING	Innovative Trial for Understanding the Impact of Targeted Therapies in NF2-Related Schwannomatosis (INTUITT-NF2)
NCT00030043	PHASE1	COMPLETED	An Implant for Hearing Loss Due to Removal of Neurofibromatosis 2 Tumors
NCT01552434	PHASE1	TERMINATED	Bevacizumab and Temsirolimus Alone or in Combination With Valproic Acid or Cetuximab in Treating Patients With Advanced or Metastatic Malignancy or Other Benign Disease
NCT05130866	PHASE2/PHASE3	TERMINATED	Efficacy and Safety of REC-2282 in Patients With Progressive Neurofibromatosis Type 2 (NF2) Mutated Meningiomas
NCT05521048	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Doxycycline in Cutaneous Schwannoma (NF2)
NCT07131722	PHASE1/PHASE2	NOT_YET_RECRUITING	Study to Determine Optimal Dose, Evaluate the Efficacy and Safety of PRG-N-01 in Patients With Neurofibromatosis Type II
NCT00863122	EARLY_PHASE1	COMPLETED	Concentration and Activity of Lapatinib in Vestibular Schwannomas
NCT01880749	EARLY_PHASE1	COMPLETED	Exploring the Activity of RAD001 in Vestibular Schwannomas and Meningiomas
NCT02282917	EARLY_PHASE1	TERMINATED	Exploratory Evaluation of AR-42 Histone Deacetylase Inhibitor in the Treatment of Vestibular Schwannoma and Meningioma
NCT00004483	Not specified	UNKNOWN	NF2 Natural History Consortium
NCT01885767	Not specified	RECRUITING	Neurofibromatosis (NF) Registry Portal
NCT02246231	Not specified	COMPLETED	Effect of Implant Position on Magnetic Resonance Image Distortion
NCT02298270	Not specified	COMPLETED	Resiliency Training for Patients With Neurofibromatosis Via Videoconferencing With Skype
NCT02589912	Not specified	NO_LONGER_AVAILABLE	Compassionate Use Arm - ABI541 ABI for 10 NF2 Patients
NCT02811718	Not specified	COMPLETED	Resiliency Training for Patients With NF2 Via Videoconferencing With Skype
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT03210285	Not specified	COMPLETED	WES of NF2-associated in Comparison to Sporadic Vestibular Schwannomas - Correlation With Clinical Data
NCT03406208	Not specified	COMPLETED	Resiliency Training for Adults With Neurofibromatosis Via Live Videoconferencing
NCT03617276	Not specified	COMPLETED	Reliability of Functional Outcome Measures in Neurofibromatosis 2
NCT03893643	Not specified	UNKNOWN	Cutaneous and Mucosal Manifestations of Neurofribromatosis Type 2 in Children Under 15
NCT04890132	Not specified	UNKNOWN	Vestibular Precision: Physiology & Pathophysiology
NCT05685836	Not specified	UNKNOWN	89Zr-Bevacizumab PET/CT Imaging in NF2 Patients
NCT07420751	Not specified	ACTIVE_NOT_RECRUITING	Assessment of Patient Experience With Auto-Captioning Glasses in NF2-Related-Schwannomatosis