AP1S2

Summary

AP1S2 (adaptor related protein complex 1 subunit sigma 2, HGNC:560) is a protein-coding gene on chromosome Xp22.2, encoding AP-1 complex subunit sigma-2 (P56377). 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. It is haploinsufficient (ClinGen: sufficient evidence).

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 the small subunit of this complex and is a member of the adaptin protein family. Transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 8905 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked syndromic complex neurodevelopmental disorder (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 115 total — 18 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 75
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001272071

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:560
Approved symbol	AP1S2
Name	adaptor related protein complex 1 subunit sigma 2
Location	Xp22.2
Locus type	gene with protein product
Status	Approved
Aliases	SIGMA1B
Ensembl gene	ENSG00000182287
Ensembl biotype	protein_coding
OMIM	300629
Entrez	8905

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 8 protein_coding, 6 nonsense_mediated_decay

ENST00000329235, ENST00000380291, ENST00000450644, ENST00000452376, ENST00000479184, ENST00000545766, ENST00000671830, ENST00000672063, ENST00000672987, ENST00000673445, ENST00000673591, ENST00000879494, ENST00000879495, ENST00000944531

RefSeq mRNA: 5 — MANE Select: NM_001272071 NM_001272071, NM_001368994, NM_001369007, NM_001369008, NM_003916

CCDS: CCDS14173, CCDS75958, CCDS94559, CCDS94560, CCDS94561

Canonical transcript exons

ENST00000672987 — 6 exons

Exon	Start	End
ENSE00001313824	15845903	15846011
ENSE00001325090	15825806	15827372
ENSE00003615434	15845379	15845516
ENSE00003743980	15828192	15828200
ENSE00003759225	15852346	15852524
ENSE00003891781	15854688	15854813

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 99.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 38.0809 / max 382.2429, expressed in 1795 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
198551	35.8343	1793
198549	1.7820	769
198550	0.4645	243

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	99.95	gold quality
cauda epididymis	UBERON:0004360	99.50	gold quality
monocyte	CL:0000576	99.26	gold quality
pigmented layer of retina	UBERON:0001782	99.14	gold quality
mononuclear cell	CL:0000842	99.04	gold quality
leukocyte	CL:0000738	98.98	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.34	gold quality
heart right ventricle	UBERON:0002080	98.32	gold quality
biceps brachii	UBERON:0001507	98.05	gold quality
pons	UBERON:0000988	97.67	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.62	gold quality
ganglionic eminence	UBERON:0004023	97.55	gold quality
granulocyte	CL:0000094	97.54	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.49	gold quality
deltoid	UBERON:0001476	97.12	gold quality
diaphragm	UBERON:0001103	97.08	gold quality
left ventricle myocardium	UBERON:0006566	96.93	gold quality
vastus lateralis	UBERON:0001379	96.83	gold quality
skeletal muscle tissue	UBERON:0001134	96.81	gold quality
trabecular bone tissue	UBERON:0002483	96.70	gold quality
muscle organ	UBERON:0001630	96.61	gold quality
quadriceps femoris	UBERON:0001377	96.59	gold quality
triceps brachii	UBERON:0001509	96.56	gold quality
gluteal muscle	UBERON:0002000	96.55	gold quality
muscle of leg	UBERON:0001383	96.52	gold quality
trigeminal ganglion	UBERON:0001675	96.46	gold quality
gastrocnemius	UBERON:0001388	96.40	gold quality
seminal vesicle	UBERON:0000998	96.26	gold quality
muscle tissue	UBERON:0002385	96.23	gold quality
tibialis anterior	UBERON:0001385	96.19	gold quality

Single-cell (SCXA)

Detected in 28 experiment(s), a significant marker in 24.

Experiment	Marker?	Max mean expression
E-GEOD-124472	yes	578.09
E-HCAD-4	yes	206.56
E-GEOD-134144	yes	43.07
E-MTAB-10553	yes	42.48
E-MTAB-6701	yes	40.73
E-HCAD-11	yes	34.62
E-HCAD-6	yes	33.83
E-HCAD-10	yes	32.54
E-MTAB-9467	yes	31.53
E-MTAB-9221	yes	27.52
E-MTAB-6678	yes	26.11
E-CURD-112	yes	25.89
E-MTAB-8410	yes	25.00
E-HCAD-13	yes	21.92
E-GEOD-135922	yes	20.47

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

98 targeting AP1S2, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-129-5P	99.88	70.26	3273

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 8)

• A mutation in the 3d intron causes skipping of exon 3 yielding a protein with 3 new AAs terminating at codon 64. A new nonsense mutation p.Gln66X was found in exon 3. Without AP1S2, defective membrane protein trafficking alters brain neural cell fate. (PMID:17617514)
• absence of an AP-1 defect in peripheral tissues is due to functional redundancy among AP-1 subunits (PMID:18428203)
• The AP1S2 c.426+1 G>T mutation segregates with the disease in the Pettigrew syndrome family. (PMID:23756445)
• sigma1B adaptin regulates adipogenesis by mediating the sorting of sortilin in adipose tissue. (PMID:24928897)
• Four generations in Chinese pedigree with Pettigrew syndrome resulting from a novel splice site mutation in AP1S2. AP1S2 mutations appear to be an important cause of Mental retardation,delayed in walking, abnormal speech, hypotonia, dysmorphic features, abnormal behavior and brain. (PMID:30714330)
• Long noncoding RNA LINC00518 acts as a competing endogenous RNA to promote the metastasis of malignant melanoma via miR-204-5p/AP1S2 axis. (PMID:31712557)
• MiR-204-5p-targeted AP1S2 is necessary for papillary thyroid carcinoma. (PMID:37328093)
• A novel AP1S2 variant causing leaky splicing in X-linked intellectual disability: Further delineation and intrafamilial variability. (PMID:38682877)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ap1s2	ENSDARG00000058504
mus_musculus	Ap1s2	ENSMUSG00000031367
rattus_norvegicus	Ap1s2	ENSRNOG00000038686
drosophila_melanogaster	AP-1sigma	FBGN0039132
caenorhabditis_elegans		WBGENE00000159

Paralogs (6): AP2S1 (ENSG00000042753), AP4S1 (ENSG00000100478), AP1S1 (ENSG00000106367), AP1S3 (ENSG00000152056), AP3S2 (ENSG00000157823), AP3S1 (ENSG00000177879)

Protein

Protein identifiers

AP-1 complex subunit sigma-2 — P56377 (reviewed: P56377)

Alternative names: Adaptor protein complex AP-1 subunit sigma-1B, Adaptor-related protein complex 1 subunit sigma-1B, Clathrin assembly protein complex 1 sigma-1B small chain, Golgi adaptor HA1/AP1 adaptin sigma-1B subunit, Sigma 1B subunit of AP-1 clathrin, Sigma-adaptin 1B, Sigma1B-adaptin

All UniProt accessions (9): P56377, A0A5F9ZHW1, A0A5F9ZHX2, A0A5F9ZI43, A6NH01, F6SFB5, H0Y673, H7BZG6, Q549M9

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). Binds to MUC1.

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

Tissue specificity. Widely expressed.

Disease relevance. Pettigrew syndrome (PGS) [MIM:304340] An X-linked syndrome characterized by intellectual disability and additional highly variable features, including choreoathetosis, hydrocephalus, Dandy-Walker malformation, seizures, and iron or calcium deposition in the brain. Intellectual disability is characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the adaptor complexes small subunit family.

Isoforms (2)

UniProt ID	Names	Canonical?
P56377-1	1	yes
P56377-2	2

RefSeq proteins (5): NP_001259000, NP_001355923, NP_001355936, NP_001355937, NP_003907 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000804	Clathrin_sm-chain_CS	Conserved_site
IPR011012	Longin-like_dom_sf	Homologous_superfamily
IPR016635	AP_complex_ssu	Family
IPR022775	AP_mu_sigma_su	Domain
IPR044733	AP1_sigma	Family

Pfam: PF01217

UniProt features (7 total): sequence conflict 4, splice variant 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P56377-F1	94.36	0.91

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: 524 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, E2F_Q4_01, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOCC_VACUOLAR_MEMBRANE, NKX25_02, GOBP_VESICLE_ORGANIZATION, AREB6_03, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_CELLULAR_PIGMENTATION, KEGG_LYSOSOME, MODULE_264

GO Biological Process (5): intracellular protein transport (GO:0006886), vesicle-mediated transport (GO:0016192), platelet dense granule organization (GO:0060155), melanosome assembly (GO:1903232), protein transport (GO:0015031)

GO Molecular Function (2): clathrin-cargo adaptor activity (GO:0035615), protein binding (GO:0005515)

GO Cellular Component (15): Golgi membrane (GO:0000139), lysosomal membrane (GO:0005765), early endosome (GO:0005769), Golgi apparatus (GO:0005794), cytosol (GO:0005829), clathrin-coated pit (GO:0005905), AP-type membrane coat adaptor complex (GO:0030119), 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), 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
intracellular protein localization	2
transport	2
endomembrane system	2
membrane protein complex	2
protein transport	1
intracellular transport	1
cellular process	1
secretory granule organization	1
melanosome organization	1
organelle assembly	1
establishment of protein localization	1
clathrin binding	1
cargo adaptor activity	1
binding	1
Golgi apparatus	1
bounding membrane of organelle	1
lysosome	1
lytic vacuole membrane	1
endosome	1
intracellular membrane-bounded organelle	1
membrane	1
membrane coat	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
intracellular vesicle	1

Protein interactions and networks

STRING

1194 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AP1S2	AP1M1	Q9BXS5	956
AP1S2	AP1G2	O75843	939
AP1S2	AP1B1	P78436	819
AP1S2	AP1M2	Q9Y6Q5	778
AP1S2	TMEM107	Q6UX40	581
AP1S2	CCDC88C	Q9P219	522
AP1S2	MSANTD4	Q8NCY6	479
AP1S2	AP1G1	O43747	464
AP1S2	TYR	P14679	454
AP1S2	MAGEB17	A8MXT2	452
AP1S2	SORT1	Q99523	446
AP1S2	TMSB4Y	O14604	437
AP1S2	CA5B	Q9Y2D0	437
AP1S2	WWC3	Q9ULE0	427
AP1S2	RAP2B	P17964	421

IntAct

40 interactions, top by confidence:

A	B	Type	Score
AP1S2	AP1G1	psi-mi:“MI:0915”(physical association)	0.670
AP1S2	AP1G1	psi-mi:“MI:0914”(association)	0.670
AP1G1	AP1S2	psi-mi:“MI:0915”(physical association)	0.660
AP1S2	AP1G1	psi-mi:“MI:0914”(association)	0.660
CORT	MB	psi-mi:“MI:0914”(association)	0.560
AP1S2	MAB21L2	psi-mi:“MI:0915”(physical association)	0.560
POTEB3	POTEF	psi-mi:“MI:0914”(association)	0.530
PI4K2A	GABARAP	psi-mi:“MI:0914”(association)	0.530
TNS2	AP1S2	psi-mi:“MI:0915”(physical association)	0.370
AP1S2	SLC43A3	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
DLD	NFKBIE	psi-mi:“MI:0914”(association)	0.350
CAV3	SHTN1	psi-mi:“MI:0914”(association)	0.350
AP2M1	C1orf226	psi-mi:“MI:0914”(association)	0.350
PPP6R2	POLRMT	psi-mi:“MI:0914”(association)	0.350
RNF13	AP3D1	psi-mi:“MI:0914”(association)	0.350
AP1M2	AP1G1	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
POTEB3	POTEB	psi-mi:“MI:0914”(association)	0.350
POTEG	POTEF	psi-mi:“MI:0914”(association)	0.350
AP2B1	SYNJ1	psi-mi:“MI:0914”(association)	0.350
COMT	AP1G1	psi-mi:“MI:0914”(association)	0.350

BioGRID (112): AP1S2 (Two-hybrid), AP1S2 (Affinity Capture-MS), AP1S2 (Affinity Capture-MS), AP1S2 (Affinity Capture-MS), AP1G1 (Co-fractionation), AP1S2 (Co-fractionation), AP1S2 (Co-fractionation), AP1S2 (Co-fractionation), AP1S2 (Two-hybrid), AP1S2 (Affinity Capture-MS), AP1B1 (Affinity Capture-MS), AP2B1 (Affinity Capture-MS), AP1G1 (Affinity Capture-MS), CLTA (Affinity Capture-MS), CPS1 (Affinity Capture-MS)

ESM2 similar proteins: B0G185, O02173, O17901, O23685, O43041, O50016, O82201, P35181, P35604, P47064, P53290, P53680, P56377, P61923, P61924, P61966, P61967, P62743, P62744, Q00381, Q09905, Q17QC5, Q1JQ98, Q28IG8, Q3ZBB6, Q3ZBS3, Q4ICG5, Q4WS49, Q54H39, Q54NZ4, Q54WW3, Q553S2, Q557G3, Q59QC5, Q5BFF8, Q5R5F2, Q5R940, Q5ZKP4, Q75F71, Q7SAQ1

Diamond homologs: B0G185, O23685, O50016, O82201, P35181, P47064, P53680, P56377, P59780, P61966, P61967, P62743, P62744, Q00381, Q09905, Q17QC5, Q1JQ98, Q1JQA3, Q2YDH6, Q3ZBB6, Q3ZBS3, Q4ICG5, Q4WS49, Q54H39, Q54NZ4, Q54WW3, Q553S2, Q5BFF8, Q5R940, Q5RDP9, Q75F71, Q7SAQ1, Q7TN05, Q84WL9, Q8BSZ2, Q8LEZ8, Q8VZ37, Q92572, Q96PC3, Q9DB50

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 35 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
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	5	151.1×	8e-09
The role of Nef in HIV-1 replication and disease pathogenesis	5	151.1×	8e-09
Host Interactions of HIV factors	5	80.0×	2e-07
HIV Infection	5	28.3×	2e-05
MHC class II antigen presentation	5	21.2×	7e-05
Membrane Trafficking	6	10.6×	3e-04
Vesicle-mediated transport	6	9.9×	4e-04
Viral Infection Pathways	6	8.8×	6e-04

GO biological processes:

GO term	Partners	Fold	FDR
vesicle-mediated transport	6	20.6×	6e-05
intracellular protein transport	6	13.9×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	7
Uncertain significance	32
Likely benign	24
Benign	12

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
1012855	NM_001272071.2(AP1S2):c.178dup (p.Arg60fs)	Pathogenic
10777	NM_001272071.2(AP1S2):c.106C>T (p.Gln36Ter)	Pathogenic
10778	NM_001272071.2(AP1S2):c.154C>T (p.Arg52Ter)	Pathogenic
10779	NM_001272071.2(AP1S2):c.180-5_180-2del	Pathogenic
10781	NM_001272071.2(AP1S2):c.226G>T (p.Glu76Ter)	Pathogenic
140457	NM_001272071.2(AP1S2):c.426+1G>T	Pathogenic
153285	GRCh38/hg38 Xp22.2-22.13(chrX:15789793-18902428)x1	Pathogenic
1756051	NM_001272071.2(AP1S2):c.68C>G (p.Ser23Ter)	Pathogenic
2442357	NM_001272071.2(AP1S2):c.288+1G>A	Pathogenic
2446573	NM_001272071.2(AP1S2):c.367C>T (p.Gln123Ter)	Pathogenic
280826	NM_001272071.2(AP1S2):c.92del (p.Thr31fs)	Pathogenic
3251646	NM_001272071.2(AP1S2):c.319del (p.Glu107fs)	Pathogenic
397541	NM_001272071.2(AP1S2):c.1-3C>A	Pathogenic
434219	NM_001272071.2(AP1S2):c.281del (p.Phe94fs)	Pathogenic
449725	NM_001272071.2(AP1S2):c.289-2A>G	Pathogenic
504198	NM_001272071.2(AP1S2):c.40C>T (p.Arg14Ter)	Pathogenic
988587	NM_001272071.2(AP1S2):c.1-2A>G	Pathogenic
992877	NM_001272071.2(AP1S2):c.54G>A (p.Trp18Ter)	Pathogenic
10780	NM_001272071.2(AP1S2):c.288+5G>A	Likely pathogenic
2444373	NM_001272071.2(AP1S2):c.21del (p.Phe7fs)	Likely pathogenic
2780458	NM_001272071.2(AP1S2):c.179+1G>A	Likely pathogenic
3898008	NM_001272071.2(AP1S2):c.357del (p.Glu121fs)	Likely pathogenic
4075752	NM_001272071.2(AP1S2):c.4C>T (p.Gln2Ter)	Likely pathogenic
4293012	NM_001272071.2(AP1S2):c.65del (p.Leu22fs)	Likely pathogenic
972700	NM_001272071.2(AP1S2):c.321_334del (p.Glu107fs)	Likely pathogenic

SpliceAI

1064 predictions. Top by Δscore:

Variant	Effect	Δscore
X:15845373:GCTTA:G	donor_loss	1.0000
X:15845374:CTTAC:C	donor_loss	1.0000
X:15845375:TTA:T	donor_loss	1.0000
X:15845376:TACCT:T	donor_loss	1.0000
X:15845377:A:AC	donor_gain	1.0000
X:15845377:ACC:A	donor_loss	1.0000
X:15845377:ACCT:A	donor_gain	1.0000
X:15845378:C:CC	donor_gain	1.0000
X:15845378:C:CT	donor_loss	1.0000
X:15845378:CCT:C	donor_gain	1.0000
X:15845378:CCTC:C	donor_gain	1.0000
X:15845512:CAGAC:C	acceptor_gain	1.0000
X:15845513:AGAC:A	acceptor_gain	1.0000
X:15845513:AGACC:A	acceptor_gain	1.0000
X:15845514:GAC:G	acceptor_gain	1.0000
X:15845514:GACCT:G	acceptor_gain	1.0000
X:15845515:AC:A	acceptor_gain	1.0000
X:15845515:ACCT:A	acceptor_loss	1.0000
X:15845515:ACCTG:A	acceptor_gain	1.0000
X:15845516:CC:C	acceptor_gain	1.0000
X:15845516:CCTGA:C	acceptor_gain	1.0000
X:15845517:C:CC	acceptor_gain	1.0000
X:15845898:CTCA:C	donor_loss	1.0000
X:15845900:CACAC:C	donor_loss	1.0000
X:15845901:A:AC	donor_gain	1.0000
X:15845902:C:CC	donor_gain	1.0000
X:15845902:C:T	donor_loss	1.0000
X:15845902:CA:C	donor_gain	1.0000
X:15845902:CACT:C	donor_gain	1.0000
X:15845902:CACTG:C	donor_gain	1.0000

AlphaMissense

1051 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:15845493:A:C	F104L	1.000
X:15845493:A:T	F104L	1.000
X:15845495:A:G	F104L	1.000
X:15845497:A:T	I103N	1.000
X:15845503:T:A	D101V	1.000
X:15845503:T:G	D101A	1.000
X:15845506:A:G	L100P	1.000
X:15845506:A:T	L100Q	1.000
X:15845508:T:A	E99D	1.000
X:15845508:T:G	E99D	1.000
X:15845509:T:A	E99V	1.000
X:15845510:C:T	E99K	1.000
X:15845512:C:T	C98Y	1.000
X:15845909:G:C	F94L	1.000
X:15845909:G:T	F94L	1.000
X:15845911:A:G	F94L	1.000
X:15845922:A:G	L90P	1.000
X:15846000:A:G	L64P	1.000
X:15846000:A:T	L64Q	1.000
X:15846002:A:C	S63R	1.000
X:15846002:A:T	S63R	1.000
X:15846004:T:G	S63R	1.000
X:15846006:G:T	A62D	1.000
X:15852355:A:T	V57D	1.000
X:15852481:A:G	L15P	1.000
X:15845487:A:C	F106L	0.999
X:15845487:A:T	F106L	0.999
X:15845489:A:G	F106L	0.999
X:15845494:A:G	F104S	0.999
X:15845495:A:C	F104V	0.999

dbSNP variants (sampled 300 via entrez): RS1000096962 (X:15843987 T>C), RS1000411799 (X:15840752 G>A), RS1000420555 (X:15853580 A>C), RS1000916756 (X:15829601 A>T), RS1001025441 (X:15844083 A>C), RS1001123686 (X:15830048 A>G), RS1001627441 (X:15837631 G>A), RS1001634559 (X:15837826 C>T), RS1001866438 (X:15850882 T>C), RS1001919037 (X:15837166 A>G), RS1002524096 (X:15844678 A>C), RS1002549632 (X:15850207 A>T), RS1002586692 (X:15831139 G>A), RS1002613901 (X:15840542 C>G,T), RS1002626482 (X:15856723 G>A)

Disease associations

OMIM: gene MIM:300629 | disease phenotypes: MIM:304340, MIM:309510

GenCC curated gene-disease

Disease	Classification	Inheritance
syndromic X-linked intellectual disability 5	Definitive	X-linked
fried syndrome	Supportive	X-linked
autism spectrum disorder	Limited	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
X-linked syndromic complex neurodevelopmental disorder	Definitive	XL

Mondo (5): syndromic X-linked intellectual disability 5 (MONDO:0010574), intellectual disability (MONDO:0001071), X-linked syndromic intellectual disability (MONDO:0020119), fried syndrome (MONDO:0019428), autism spectrum disorder (MONDO:0005258)

Orphanet (5): X-linked intellectual disability-Dandy-Walker malformation-basal ganglia disease-seizures syndrome (Orphanet:1568), X-linked intellectual disability-hypotonia-facial dysmorphism-aggressive behavior syndrome (Orphanet:85329), Fried syndrome (Orphanet:85335), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), OBSOLETE: X-linked syndromic intellectual disability (Orphanet:98464)

HPO phenotypes

75 total (30 of 75 shown, HPO-id order):

HPO	Term
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000154	Wide mouth
HP:0000194	Open mouth
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000276	Long face
HP:0000280	Coarse facial features
HP:0000303	Mandibular prognathia
HP:0000322	Short philtrum
HP:0000325	Triangular face
HP:0000331	Short chin
HP:0000348	High forehead
HP:0000365	Hearing impairment
HP:0000400	Macrotia
HP:0000407	Sensorineural hearing impairment
HP:0000411	Protruding ear
HP:0000448	Prominent nose
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000587	Abnormal optic nerve morphology
HP:0000648	Optic atrophy
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008481_11	Lung function (FEV1/FVC)	4.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases expression	6
trichostatin A	affects cotreatment, decreases expression	3
Acetaminophen	affects expression, increases expression	3
Tretinoin	decreases expression, increases expression	3
bisphenol A	increases expression, affects cotreatment	2
Temozolomide	increases expression, affects response to substance	2
Decitabine	affects expression, increases expression	2
Cisplatin	affects expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression, increases expression	2
Tetrachlorodibenzodioxin	decreases expression, increases expression	2
Cyclosporine	decreases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment	2
tris(2-butoxyethyl) phosphate	affects expression	1
methylparaben	decreases expression	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
beta-methylcholine	affects expression	1
tamibarotene	increases expression	1
cylindrospermopsin	decreases 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	affects cotreatment, decreases expression, increases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
bisphenol S	affects cotreatment, increases expression	1
Pioglitazone	decreases expression	1
Zoledronic Acid	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Carmustine	affects response to substance	1
Demecolcine	decreases expression	1

Cellosaurus cell lines

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

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

Cellosaurus	Name	Category	Sex
CVCL_5J64	GM12523	Transformed cell line	Male
CVCL_5J75	GM12534	Transformed cell line	Male
CVCL_5J82	GM12543	Transformed cell line	Female
CVCL_SC74	HAP1 AP1S2 (-) 1	Cancer cell line	Male
CVCL_SC75	HAP1 AP1S2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders