AP2S1 Gene

Name	adaptor-related protein complex 2, sigma 1 subunit
Description	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. [provided by RefSeq, Jul 2014]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The adaptor‐related protein complex 2 sigma subunit (AP2S1) is a critical component of the heterotetrameric AP2 complex that mediates clathrin‐dependent endocytosis of transmembrane proteins. In several studies, AP2S1 was shown to recognize and bind specific dileucine‐based motifs present in cargo proteins, such as the calcium‐sensing receptor (CaSR), thereby facilitating receptor internalization and correct intracellular signaling. Mutations in AP2S1—especially those affecting the highly conserved arginine at position 15—disrupt the interaction between AP2 and its cargo, leading to impaired CaSR endocytosis and altered calcium homeostasis. Such loss‐of‐function mutations are causally linked with familial hypocalciuric hypercalcemia type 3 (FHH3), a disorder characterized by marked hypercalcemia, hypermagnesemia, and associated phenotypes. Complementary in vitro and in vivo models have confirmed that disruption of the AP2S1 subunit significantly diminishes the sensitivity of CaSR‐expressing cells to extracellular calcium and alters downstream signaling, while targeted pharmacological intervention (for example, with positive allosteric modulators) can partially ameliorate the calcitropic defect."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": " Furthermore, mouse models engineered to harbor corresponding AP2S1 mutations recapitulate the biochemical derangements seen in humans, thereby establishing the in vivo relevance of AP2S1 in extracellular calcium regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In addition to its role in CaSR trafficking, AP2S1 has been implicated in other cellular processes, including synaptic vesicle recycling and regulation of growth factor signaling pathways, highlighting its broader significance in endocytic control and cellular homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "M Andrew Nesbit, Fadil M Hannan, Sarah A Howles, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations affecting G-protein subunit α11 in hypercalcemia and hypocalcemia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "N Engl J Med (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1056/NEJMoa1300253"}], "href": "https://doi.org/10.1056/NEJMoa1300253"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23802516"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23802516"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "M Andrew Nesbit, Fadil M Hannan, Sarah A Howles, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.2492"}], "href": "https://doi.org/10.1038/ng.2492"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23222959"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23222959"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Fadil M Hannan, Sarah A Howles, Angela Rogers, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddv226"}], "href": "https://doi.org/10.1093/hmg/ddv226"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26082470"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26082470"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Geoffrey N Hendy, Lucie Canaff, Ron S Newfield, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Codon Arg15 mutations of the AP2S1 gene: common occurrence in familial hypocalciuric hypercalcemia cases negative for calcium-sensing receptor (CASR) mutations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Endocrinol Metab (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/jc.2014-1120"}], "href": "https://doi.org/10.1210/jc.2014-1120"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24731014"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24731014"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Fadil M Hannan, Mark Stevenson, Asha L Bayliss, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ap2s1 mutation causes hypercalcaemia in mice and impairs interaction between calcium-sensing receptor and adaptor protein-2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddab076"}], "href": "https://doi.org/10.1093/hmg/ddab076"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33729479"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33729479"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Angela Rogers, M Andrew Nesbit, Fadil M Hannan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutational analysis of the adaptor protein 2 sigma subunit (AP2S1) gene: search for autosomal dominant hypocalcemia type 3 (ADH3)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Endocrinol Metab (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/jc.2013-3909"}], "href": "https://doi.org/10.1210/jc.2013-3909"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24708097"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24708097"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Saumitra Dey Choudhury, Zeeshan Mushtaq, Suneel Reddy-Alla, et al. "}, {"type": "b", "children": [{"type": "t", "text": "σ2-Adaptin Facilitates Basal Synaptic Transmission and Is Required for Regenerating Endo-Exo Cycling Pool Under High-Frequency Nerve Stimulation in Drosophila."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genetics (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1534/genetics.115.183863"}], "href": "https://doi.org/10.1534/genetics.115.183863"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26920756"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26920756"}]}]}]}
Synonyms	CLAPS2, HHC3, FBH3, FBHOK, AP17
Proteins	AP2S1_HUMAN
NCBI Gene ID	1175
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

AP2S1 has 8,079 functional associations with biological entities spanning 9 categories (molecular profile, organism, chemical, disease, phenotype or trait, functional term, phrase or reference, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 124 datasets.

Click the + buttons to view associations for AP2S1 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

AP2S1 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Achilles Cell Line Gene Essentiality Profiles	cell lines with fitness changed by AP2S1 gene knockdown relative to other cell lines from the Achilles Cell Line Gene Essentiality Profiles dataset.
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of AP2S1 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of AP2S1 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of AP2S1 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of AP2S1 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of AP2S1 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of AP2S1 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of AP2S1 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of AP2S1 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of AP2S1 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of AP2S1 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of AP2S1 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of AP2S1 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with AP2S1 protein from the CCLE Cell Line Proteomics dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of AP2S1 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of AP2S1 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of AP2S1 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	ClinVar Gene-Phenotype Associations	phenotypes associated with AP2S1 gene from the curated ClinVar Gene-Phenotype Associations dataset.
	ClinVar Gene-Phenotype Associations 2025	phenotypes associated with AP2S1 gene from the curated ClinVar Gene-Phenotype Associations 2025 dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of AP2S1 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing AP2S1 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing AP2S1 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with AP2S1 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with AP2S1 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of AP2S1 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with AP2S1 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with AP2S1 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with AP2S1 gene/protein from the curated CTD Gene-Disease Associations dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with AP2S1 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with AP2S1 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with AP2S1 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with AP2S1 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with AP2S1 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at AP2S1 gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of AP2S1 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of AP2S1 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing AP2S1 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GDSC Cell Line Gene Expression Profiles	cell lines with high or low expression of AP2S1 gene relative to other cell lines from the GDSC Cell Line Gene Expression Profiles dataset.
	GeneRIF Biological Term Annotations	biological terms co-occuring with AP2S1 gene in literature-supported statements describing functions of genes from the GeneRIF Biological Term Annotations dataset.
	GeneSigDB Published Gene Signatures	PubMedIDs of publications reporting gene signatures containing AP2S1 from the GeneSigDB Published Gene Signatures dataset.