AP2S1

Summary

AP2S1 (adaptor related protein complex 2 subunit sigma 1, HGNC:565) is a protein-coding gene on chromosome 19q13.32, encoding AP-2 complex subunit sigma (P53680). Component of the adaptor protein complex 2 (AP-2). It is a selective cancer dependency (DepMap: 74.3% of cell lines).

One of two major clathrin-associated adaptor complexes, AP-2, is a heterotetramer which is associated with the plasma membrane. This complex is composed of two large chains, a medium chain, and a small chain. This gene encodes the small chain of this complex. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 1175 — RefSeq curated summary.

At a glance

• Gene–disease (curated): familial hypocalciuric hypercalcemia 3 (Strong, GenCC) — +3 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 152 total — 5 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 20
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 74.3% of screened cell lines
• MANE Select transcript: NM_004069

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:565
Approved symbol	AP2S1
Name	adaptor related protein complex 2 subunit sigma 1
Location	19q13.32
Locus type	gene with protein product
Status	Approved
Aliases	FBHOk, FBH3
Ensembl gene	ENSG00000042753
Ensembl biotype	protein_coding
OMIM	602242
Entrez	1175

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 14 protein_coding, 3 retained_intron

ENST00000263270, ENST00000352203, ENST00000593442, ENST00000597020, ENST00000597421, ENST00000598027, ENST00000599990, ENST00000600964, ENST00000601498, ENST00000601649, ENST00000869561, ENST00000930898, ENST00000930899, ENST00000930900, ENST00000930901, ENST00000960448, ENST00000960449

RefSeq mRNA: 5 — MANE Select: NM_004069 NM_001301076, NM_001301078, NM_001301081, NM_004069, NM_021575

CCDS: CCDS12693, CCDS33062, CCDS77321, CCDS77322, CCDS77323

Canonical transcript exons

ENST00000263270 — 5 exons

Exon	Start	End
ENSE00000714235	46839465	46839578
ENSE00000858310	46845993	46846142
ENSE00001048906	46850764	46850846
ENSE00003064228	46838167	46838548
ENSE00003553991	46838740	46838799

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 98.41.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 147.5002 / max 515.8357, expressed in 1827 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
181705	120.5103	1827
181704	19.7351	1771
181703	3.3660	1120
181702	2.3377	967
181699	0.7200	382
181700	0.3596	180
181706	0.3549	194
181701	0.1166	43

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	98.41	gold quality
stromal cell of endometrium	CL:0002255	98.32	gold quality
right adrenal gland	UBERON:0001233	98.32	gold quality
right frontal lobe	UBERON:0002810	98.28	gold quality
mucosa of transverse colon	UBERON:0004991	98.28	gold quality
penis	UBERON:0000989	98.26	gold quality
esophagus mucosa	UBERON:0002469	98.25	gold quality
left adrenal gland	UBERON:0001234	98.23	gold quality
right adrenal gland cortex	UBERON:0035827	98.23	gold quality
prefrontal cortex	UBERON:0000451	98.18	gold quality
left adrenal gland cortex	UBERON:0035825	98.18	gold quality
cingulate cortex	UBERON:0003027	98.10	gold quality
adrenal cortex	UBERON:0001235	98.08	gold quality
skin of leg	UBERON:0001511	98.08	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.07	gold quality
amygdala	UBERON:0001876	98.05	gold quality
anterior cingulate cortex	UBERON:0009835	98.05	gold quality
mammalian vulva	UBERON:0000997	98.02	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.99	gold quality
adult organism	UBERON:0007023	97.97	gold quality
pharyngeal mucosa	UBERON:0000355	97.96	gold quality
skin of abdomen	UBERON:0001416	97.95	gold quality
granulocyte	CL:0000094	97.94	gold quality
nipple	UBERON:0002030	97.94	gold quality
pons	UBERON:0000988	97.92	gold quality
monocyte	CL:0000576	97.91	gold quality
left coronary artery	UBERON:0001626	97.87	gold quality
nucleus accumbens	UBERON:0001882	97.86	gold quality
coronary artery	UBERON:0001621	97.85	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.84	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	80.34
E-CURD-122	yes	65.10
E-MTAB-6701	yes	51.85
E-MTAB-8410	yes	43.04
E-GEOD-135922	yes	42.47
E-CURD-46	yes	33.33
E-CURD-88	yes	22.19
E-CURD-112	yes	20.27
E-HCAD-1	yes	18.05
E-HCAD-9	yes	16.08
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

11 targeting AP2S1, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-6744-3P	99.22	64.41	972
HSA-MIR-4757-5P	99.12	64.51	981
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-6749-3P	99.00	65.73	1443
HSA-MIR-4755-3P	98.77	65.59	1915
HSA-MIR-5589-5P	98.34	64.82	1148
HSA-MIR-4642	97.52	67.60	916

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 74.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 10)

• Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3. (PMID:23222959)
• None of the 60 patients presented with nucleotidic changes or copy number variation in the AP2S1 gene, thereby excluding AP2S1 defects as a frequent cause of isolated hypoparathyroidism. (PMID:24423332)
• The absence of AP2S1 abnormalities in hypocalcemic patients, suggests that autosomal dominant hypocalcemia 3 (ADH3) may not occur or otherwise represents a rare hypocalcemic disorder. (PMID:24708097)
• The results affirm that a significant number of patients suspected of having Familial hypocalciuric hypercalcemia but proven negative for CASR mutation have AP2S1 p.R15 mutations. (PMID:24731014)
• our studies demonstrate AP2sigma2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue. (PMID:26082470)
• In 33 CASR-negative patients with suspected FHH, Data found two (~6%) with a mutation in AP2S1 (p.Arg15Leu and p.Arg15His). Family screening confirmed the genotype-phenotype correlations. Data did not identify any pathogenic mutations in GNA11. (PMID:27913609)
• CaSR and AP2S1 sequencing is worthwhile in patients with familial hyperparathyroidism and phenotype suggesting familial hypocalciuric hypercalcemia as it can diagnose up to 50% of cases. (PMID:28176280)
• Hypercalcemia-associated AP2sigma mutations reduced calcium-sensing receptor (CaSR) signaling via Galphaq/11 and Galphai/o pathways. The mutations also delayed CaSR internalization due to prolonged residency time of CaSR in clathrin structures that impaired or abolished endosomal signaling. (PMID:29420171)
• Mechanism of p38 MAPK-induced EGFR endocytosis and its crosstalk with ligand-induced pathways. (PMID:34032851)
• AP2S1 regulates APP degradation through late endosome-lysosome fusion in cells and APP/PS1 mice. (PMID:36412210)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ap2s1	ENSDARG00000026967
mus_musculus	Ap2s1	ENSMUSG00000008036
rattus_norvegicus	Ap2s1	ENSRNOG00000015865
drosophila_melanogaster	AP-2sigma	FBGN0043012
caenorhabditis_elegans		WBGENE00000157

Paralogs (6): AP4S1 (ENSG00000100478), AP1S1 (ENSG00000106367), AP1S3 (ENSG00000152056), AP3S2 (ENSG00000157823), AP3S1 (ENSG00000177879), AP1S2 (ENSG00000182287)

Protein

Protein identifiers

AP-2 complex subunit sigma — P53680 (reviewed: P53680)

Alternative names: Adaptor protein complex AP-2 subunit sigma, Adaptor-related protein complex 2 subunit sigma, Clathrin assembly protein 2 sigma small chain, Clathrin coat assembly protein AP17, Clathrin coat-associated protein AP17, HA2 17 kDa subunit, Plasma membrane adaptor AP-2 17 kDa protein, Sigma2-adaptin

All UniProt accessions (6): P53680, M0QYZ2, M0QZ21, M0R0N4, M0R1S0, X6R390

UniProt curated annotations — full annotation on UniProt →

Function. Component of the adaptor protein complex 2 (AP-2). Adaptor protein complexes function in protein transport via transport vesicles in different membrane traffic pathways. Adaptor protein complexes are vesicle coat components and appear to be involved in cargo selection and vesicle formation. AP-2 is involved in clathrin-dependent endocytosis in which cargo proteins are incorporated into vesicles surrounded by clathrin (clathrin-coated vesicles, CCVs) which are destined for fusion with the early endosome. The clathrin lattice serves as a mechanical scaffold but is itself unable to bind directly to membrane components. Clathrin-associated adaptor protein (AP) complexes which can bind directly to both the clathrin lattice and to the lipid and protein components of membranes are considered to be the major clathrin adaptors contributing the CCV formation. AP-2 also serves as a cargo receptor to selectively sort the membrane proteins involved in receptor-mediated endocytosis. AP-2 seems to play a role in the recycling of synaptic vesicle membranes from the presynaptic surface. AP-2 recognizes Y-X-X-[FILMV] (Y-X-X-Phi) and [ED]-X-X-X-L-[LI] endocytosis signal motifs within the cytosolic tails of transmembrane cargo molecules. AP-2 may also play a role in maintaining normal post-endocytic trafficking through the ARF6-regulated, non-clathrin pathway. The AP-2 alpha and AP-2 sigma subunits are thought to contribute to the recognition of the [ED]-X-X-X-L-[LI] motif. May also play a role in extracellular calcium homeostasis.

Subunit / interactions. Adaptor protein complex 2 (AP-2) is a heterotetramer composed of two large adaptins (alpha-type subunit AP2A1 or AP2A2 and beta-type subunit AP2B1), a medium adaptin (mu-type subunit AP2M1) and a small adaptin (sigma-type subunit AP2S1). Interacts with CCDC32; the interaction is direct and mediates association of CCDC32 with adaptor protein complex 2 (AP-2).

Subcellular location. Cell membrane. Membrane. Coated pit.

Disease relevance. Hypocalciuric hypercalcemia, familial 3 (HHC3) [MIM:600740] A form of hypocalciuric hypercalcemia, a disorder of mineral homeostasis that is transmitted as an autosomal dominant trait with a high degree of penetrance. It is characterized biochemically by lifelong elevation of serum calcium concentrations and is associated with inappropriately low urinary calcium excretion and a normal or mildly elevated circulating parathyroid hormone level. Hypermagnesemia is typically present. Affected individuals are usually asymptomatic and the disorder is considered benign. However, chondrocalcinosis and pancreatitis occur in some adults. 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?
P53680-1	1	yes
P53680-2	2

RefSeq proteins (5): NP_001288005, NP_001288007, NP_001288010, NP_004060, NP_067586 (=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
IPR027156	APS2	Family

Pfam: PF01217

UniProt features (18 total): helix 5, strand 5, sequence variant 3, sequence conflict 2, chain 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6URI	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P53680-F1	97.03	0.97

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 (1): 140

Function

Pathways and Gene Ontology

Reactome pathways

42 pathways

ID	Pathway
R-HSA-167590	Nef Mediated CD4 Down-regulation
R-HSA-177504	Retrograde neurotrophin signalling
R-HSA-182218	Nef Mediated CD8 Down-regulation
R-HSA-2132295	MHC class II antigen presentation
R-HSA-3928665	EPH-ephrin mediated repulsion of cells
R-HSA-437239	Recycling pathway of L1
R-HSA-5099900	WNT5A-dependent internalization of FZD4
R-HSA-5140745	WNT5A-dependent internalization of FZD2, FZD5 and ROR2
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-8866427	VLDLR internalisation and degradation
R-HSA-8964038	LDL clearance
R-HSA-9679191	Potential therapeutics for SARS
R-HSA-9918485	Dengue Virus Attachment and Entry
R-HSA-416993	Trafficking of GluR2-containing AMPA receptors
R-HSA-1266738	Developmental Biology
R-HSA-1280218	Adaptive Immune System
R-HSA-162582	Signal Transduction
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-166520	Signaling by NTRKs
R-HSA-168256	Immune System
R-HSA-174824	Plasma lipoprotein assembly, remodeling, and clearance
R-HSA-187037	Signaling by NTRK1 (TRKA)
R-HSA-195721	Signaling by WNT
R-HSA-199991	Membrane Trafficking
R-HSA-2682334	EPH-Ephrin signaling

MSigDB gene sets: 350 (showing top): REACTOME_RETROGRADE_NEUROTROPHIN_SIGNALLING, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOCC_VACUOLAR_MEMBRANE, MODULE_151, ENK_UV_RESPONSE_KERATINOCYTE_UP, DITTMER_PTHLH_TARGETS_UP, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, MODULE_264, REACTOME_THE_ROLE_OF_NEF_IN_HIV_1_REPLICATION_AND_DISEASE_PATHOGENESIS, GOBP_CLATHRIN_COAT_ASSEMBLY, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING

GO Biological Process (9): intracellular protein transport (GO:0006886), vesicle-mediated transport (GO:0016192), regulation of endocytosis (GO:0030100), clathrin coat assembly (GO:0048268), synaptic vesicle endocytosis (GO:0048488), clathrin-dependent endocytosis (GO:0072583), postsynaptic neurotransmitter receptor internalization (GO:0098884), endocytosis (GO:0006897), protein transport (GO:0015031)

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

GO Cellular Component (16): cytosol (GO:0005829), plasma membrane (GO:0005886), cytoplasmic side of plasma membrane (GO:0009898), AP-2 adaptor complex (GO:0030122), endocytic vesicle membrane (GO:0030666), clathrin-coated endocytic vesicle membrane (GO:0030669), endolysosome membrane (GO:0036020), clathrin-coated endocytic vesicle (GO:0045334), presynapse (GO:0098793), postsynapse (GO:0098794), cytoplasm (GO:0005737), clathrin-coated pit (GO:0005905), endomembrane system (GO:0012505), membrane (GO:0016020), membrane coat (GO:0030117), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	2
PCP/CE pathway	2
Plasma lipoprotein clearance	2
Signaling by NTRK1 (TRKA)	1
Adaptive Immune System	1
EPH-Ephrin signaling	1
L1CAM interactions	1
Clathrin-mediated endocytosis	1
Membrane Trafficking	1
SARS-CoV Infections	1
Dengue Virus Infection	1
Trafficking of AMPA receptors	1
Immune System	1
Viral Infection Pathways	1
HIV Infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
intracellular protein localization	2
transport	2
cytoplasm	2
membrane	2
plasma membrane	2
endocytic vesicle	2
synapse	2
protein transport	1
intracellular transport	1
cellular process	1
endocytosis	1
regulation of cellular component organization	1
regulation of vesicle-mediated transport	1
protein-containing complex assembly	1
synaptic vesicle recycling	1
presynaptic endocytosis	1
receptor-mediated endocytosis	1
regulation of postsynaptic membrane neurotransmitter receptor levels	1
neurotransmitter receptor internalization	1
postsynaptic endocytosis	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
establishment of protein localization	1
clathrin binding	1
cargo adaptor activity	1
binding	1
cell periphery	1
cytoplasmic side of membrane	1
clathrin coat of endocytic vesicle	1
clathrin adaptor complex	1
clathrin coat of coated pit	1
plasma membrane protein complex	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
clathrin-coated vesicle membrane	1
endocytic vesicle membrane	1
clathrin-coated endocytic vesicle	1

Protein interactions and networks

STRING

1809 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AP2S1	AP2B1	P21851	988
AP2S1	AP2M1	P20172	982
AP2S1	AP2A1	O95782	963
AP2S1	AP1M1	Q9BXS5	866
AP2S1	AP2A2	O94973	865
AP2S1	CASR	P41180	728
AP2S1	GNA11	P29992	718
AP2S1	GCM2	O75603	615
AP2S1	CDC73	Q6P1J9	614
AP2S1	CLTC	Q00610	578
AP2S1	CLTCL1	P53675	557
AP2S1	AAGAB	Q6PD74	515
AP2S1	MEN1	O00255	507
AP2S1	AP1B1	P78436	502
AP2S1	PTH	P01270	501

IntAct

109 interactions, top by confidence:

A	B	Type	Score
GRB2	EGFR	psi-mi:“MI:0914”(association)	0.980
AAGAB	AP2S1	psi-mi:“MI:0915”(physical association)	0.930
AP2S1	AAGAB	psi-mi:“MI:0915”(physical association)	0.930
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
AP2S1	AP2A2	psi-mi:“MI:0914”(association)	0.640
ITSN1	AP2S1	psi-mi:“MI:0914”(association)	0.640
SNX9	WASL	psi-mi:“MI:0914”(association)	0.640
EGFR	NDUFA4	psi-mi:“MI:0914”(association)	0.530
AP2B1	AP2A2	psi-mi:“MI:0914”(association)	0.530
EPS15	AP2A2	psi-mi:“MI:0914”(association)	0.530
NECAP2	AP2A2	psi-mi:“MI:0914”(association)	0.530
GPBP1L1	CNOT1	psi-mi:“MI:0914”(association)	0.530
ARFGAP1	AURKA	psi-mi:“MI:0914”(association)	0.530
VCAM1	PSMD11	psi-mi:“MI:0914”(association)	0.530
CFTR	CNOT1	psi-mi:“MI:0914”(association)	0.480
AP2S1	Ap2a1	psi-mi:“MI:0915”(physical association)	0.400
DNAJC5	AP2S1	psi-mi:“MI:0915”(physical association)	0.400
CRIPTO	AP2S1	psi-mi:“MI:0915”(physical association)	0.370
Dctn3		psi-mi:“MI:0914”(association)	0.350
CLTB	WNK1	psi-mi:“MI:0914”(association)	0.350
Smo	METTL8	psi-mi:“MI:0914”(association)	0.350

BioGRID (267): AAGAB (Two-hybrid), AP2S1 (Affinity Capture-MS), AP2S1 (Affinity Capture-MS), AP2S1 (Affinity Capture-MS), AP2S1 (Affinity Capture-MS), AP2A1 (Co-fractionation), AP2A2 (Co-fractionation), AP2M1 (Co-fractionation), AP2S1 (Co-fractionation), AP2S1 (Proximity Label-MS), AP2S1 (Proximity Label-MS), AP2S1 (Proximity Label-MS), AP2S1 (Affinity Capture-MS), AP2S1 (Affinity Capture-MS), AP2S1 (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

1 interactions.

A	Effect	B	Mechanism
AP2S1	“form complex”	“AP-2 complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 105 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	6	60.1×	5e-08
VLDLR internalisation and degradation	5	47.0×	3e-06
LDL clearance	5	35.8×	1e-05
Clathrin-mediated endocytosis	24	26.9×	8e-26
Cargo recognition for clathrin-mediated endocytosis	16	22.1×	3e-15
Recycling pathway of L1	7	20.6×	3e-06
PCP/CE pathway	5	19.8×	2e-04
EPH-ephrin mediated repulsion of cells	6	17.3×	5e-05

GO biological processes:

GO term	Partners	Fold	FDR
synaptic vesicle endocytosis	11	52.8×	8e-14
clathrin-dependent endocytosis	8	51.6×	9e-10
clathrin coat assembly	5	49.3×	8e-06
positive regulation of miRNA transcription	5	16.1×	2e-03
endocytosis	13	13.8×	3e-09
regulation of protein localization	5	11.4×	7e-03
actin filament organization	7	9.2×	2e-03
vesicle-mediated transport	7	7.5×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	1
Uncertain significance	43
Likely benign	77
Benign	10

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
39424	NM_004069.6(AP2S1):c.43C>T (p.Arg15Cys)	Pathogenic
39425	NM_004069.6(AP2S1):c.44G>T (p.Arg15Leu)	Pathogenic
59115	GRCh38/hg38 19q13.32-13.33(chr19:46658791-49050450)x3	Pathogenic
60103	GRCh38/hg38 19q13.32-13.33(chr19:46458122-47683579)x1	Pathogenic
625762	GRCh37/hg19 19q13.32-13.33(chr19:47036361-48525536)	Pathogenic
441540	GRCh37/hg19 19q13.32-13.33(chr19:46404248-48488721)x1	Likely pathogenic

SpliceAI

919 predictions. Top by Δscore:

Variant	Effect	Δscore
19:46838544:TAAAC:T	acceptor_gain	1.0000
19:46838545:AAAC:A	acceptor_gain	1.0000
19:46838547:AC:A	acceptor_gain	1.0000
19:46838548:CCTG:C	acceptor_gain	1.0000
19:46838549:C:CA	acceptor_loss	1.0000
19:46838549:C:CC	acceptor_gain	1.0000
19:46838551:G:C	acceptor_gain	1.0000
19:46838551:G:GC	acceptor_gain	1.0000
19:46838553:G:C	acceptor_gain	1.0000
19:46838736:CTACC:C	donor_loss	1.0000
19:46838737:TACCT:T	donor_loss	1.0000
19:46838739:C:CG	donor_loss	1.0000
19:46838795:AAGAC:A	acceptor_gain	1.0000
19:46838796:AGAC:A	acceptor_gain	1.0000
19:46838796:AGACC:A	acceptor_loss	1.0000
19:46838797:GAC:G	acceptor_gain	1.0000
19:46838798:AC:A	acceptor_gain	1.0000
19:46838798:ACC:A	acceptor_loss	1.0000
19:46838799:CC:C	acceptor_gain	1.0000
19:46838800:C:CA	acceptor_loss	1.0000
19:46838800:C:CC	acceptor_gain	1.0000
19:46838801:T:G	acceptor_loss	1.0000
19:46839460:CGTAC:C	donor_loss	1.0000
19:46839461:GTA:G	donor_loss	1.0000
19:46839462:TACCT:T	donor_loss	1.0000
19:46839463:A:AC	donor_gain	1.0000
19:46839463:A:AG	donor_loss	1.0000
19:46839463:ACCT:A	donor_gain	1.0000
19:46839464:C:CC	donor_gain	1.0000
19:46839464:C:CT	donor_loss	1.0000

AlphaMissense

944 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:46838759:A:G	L103P	1.000
19:46838765:A:G	L101P	1.000
19:46838768:T:A	E100V	1.000
19:46839538:A:G	L65P	1.000
19:46839553:C:G	R60P	1.000
19:46846103:G:T	R15S	1.000
19:46838514:C:A	G121V	0.999
19:46838514:C:T	G121D	0.999
19:46838746:G:C	F107L	0.999
19:46838746:G:T	F107L	0.999
19:46838748:A:G	F107L	0.999
19:46838752:G:C	F105L	0.999
19:46838752:G:T	F105L	0.999
19:46838754:A:G	F105L	0.999
19:46838759:A:T	L103Q	0.999
19:46838762:T:A	D102V	0.999
19:46838767:T:A	E100D	0.999
19:46838767:T:G	E100D	0.999
19:46838768:T:G	E100A	0.999
19:46838769:C:T	E100K	0.999
19:46838782:G:C	F95L	0.999
19:46838782:G:T	F95L	0.999
19:46838784:A:G	F95L	0.999
19:46839522:A:C	C70W	0.999
19:46839528:G:C	C68W	0.999
19:46839530:A:G	C68R	0.999
19:46839531:G:C	F67L	0.999
19:46839531:G:T	F67L	0.999
19:46839533:A:G	F67L	0.999
19:46839538:A:T	L65H	0.999

dbSNP variants (sampled 300 via entrez): RS1000016906 (19:46850581 C>A,G,T), RS1000088364 (19:46850259 C>G,T), RS1000152067 (19:46847114 CTT>C), RS1000218130 (19:46839909 G>C), RS1000414592 (19:46839641 G>C), RS1000457400 (19:46844804 A>C), RS1000488090 (19:46839209 C>A,G,T), RS1000695657 (19:46852040 G>GA), RS1000757455 (19:46840843 G>A,C), RS1000758958 (19:46845831 A>C), RS1000787217 (19:46840638 C>A,G), RS1001034828 (19:46845467 G>C,T), RS1001192722 (19:46846080 C>G,T), RS1001455776 (19:46843727 GA>G,GAA), RS1001532214 (19:46843740 A>T)

Disease associations

OMIM: gene MIM:602242 | disease phenotypes: MIM:600740, MIM:209850

GenCC curated gene-disease

Disease	Classification	Inheritance
familial hypocalciuric hypercalcemia 3	Strong	Autosomal dominant
neurodevelopmental disorder	Strong	Autosomal dominant
autism spectrum disorder	Limited	Autosomal dominant
complex neurodevelopmental disorder	Limited	Autosomal dominant

Mondo (5): familial hypocalciuric hypercalcemia 3 (MONDO:0010926), autism (MONDO:0005260), neurodevelopmental disorder (MONDO:0700092), autism spectrum disorder (MONDO:0005258), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (2): Familial hypocalciuric hypercalcemia type 3 (Orphanet:101050), Familial hypocalciuric hypercalcemia (Orphanet:405)

HPO phenotypes

20 total (21 of 20 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000083	Renal insufficiency
HP:0000716	Depression
HP:0000787	Nephrolithiasis
HP:0000934	Chondrocalcinosis
HP:0001012	Multiple lipomas
HP:0001324	Muscle weakness
HP:0001733	Pancreatitis
HP:0002148	Hypophosphatemia
HP:0002315	Headache
HP:0002653	Bone pain
HP:0002749	Osteomalacia
HP:0002918	Hypermagnesemia
HP:0003072	Hypercalcemia
HP:0003127	Hypocalciuria
HP:0003529	Parathormone-independent increased renal tubular calcium reabsorption
HP:0004398	Peptic ulcer
HP:0008200	Primary hyperparathyroidism
HP:0008659	Multiple small medullary renal cysts
HP:0012378	Fatigue
HP:0000717	Autism

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST010204_28	Low density lipoprotein cholesterol levels	3.000000e-08
GCST010703_65	Brain morphology (MOSTest)	2.000000e-08
GCST010727_42	Deep white matter hyperintensities	6.000000e-06
GCST012616_23	Spondylosis	1.000000e-05

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004346	neuroimaging measurement
EFO:0005665	white matter hyperintensity measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D065886	Neurodevelopmental Disorders	F03.625
C537147	Familial benign hypercalcemia, type 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066485 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.75	Kd	17.89	nM	CHEMBL5653589
7.75	ED50	17.89	nM	CHEMBL5653589
6.17	Kd	678.2	nM	CHEMBL3752910
6.17	ED50	678.2	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147867: Binding affinity to human AP2S1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0179	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147867: Binding affinity to human AP2S1 incubated for 45 mins by Kinobead based pull down assay	kd	0.6782	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	4
Cadmium	decreases reaction, increases abundance, increases palmitoylation, increases expression	2
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, increases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment	2
2,4,6-tribromophenol	decreases expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, increases reaction	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
CD 437	decreases expression	1
chloropicrin	decreases expression	1
3-(4’-hydroxy-3’-adamantylbiphenyl-4-yl)acrylic acid	decreases expression	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol AF	increases expression	1
Irinotecan	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation	1
Cisplatin	increases expression	1
Cocaine	decreases expression	1
Coumestrol	increases expression	1
Fluorouracil	affects cotreatment, decreases expression	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
CHEMBL5650909	Binding	Binding affinity to human AP2S1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

394 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
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
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