AP2S1

adaptor related protein complex 2 subunit sigma 1, the group of Adaptor related protein complex 2

Basic information

Region (hg38): 19:46838135-46850846

Previous symbols: [ "CLAPS2", "HHC3" ]

Links

ENSG00000042753 ∙ NCBI:1175 ∙ OMIM:602242 ∙ HGNC:565 ∙ Uniprot:P53680 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• familial hypocalciuric hypercalcemia 3 (Strong), mode of inheritance: AD
• familial hypocalciuric hypercalcemia 3 (Strong), mode of inheritance: AD
• familial hypocalciuric hypercalcemia 3 (Strong), mode of inheritance: AD
• autism spectrum disorder (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hypocalciuric hypercalcemia, familial, type III	AD	Endocrine	The condition can involve parathyroidectomy-refractory sequelae of hypercalcemia such as headaches, fatigue, and pain, and medical treatment (eg, with cinacalcet) has been reported as benefical related to symptoms as well as biochemical parameters	Endocrine	23222959; 27050234

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the AP2S1 gene.

• not provided (3 variants)
• Familial hypocalciuric hypercalcemia 3 (3 variants)
• AP2S1-related disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the AP2S1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				30		30
missense	3		18			21
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region			5	7	1	13
non coding			3	32	9	44
Total	3	0	21	62	9

Variants in AP2S1

This is a list of pathogenic ClinVar variants found in the AP2S1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
19-46838160-C-T			Likely benign (Nov 10, 2018)
19-46838237-G-A			Benign (Nov 10, 2018)
19-46838377-C-T			Likely benign (Oct 03, 2020)
19-46838489-C-T		Familial hypocalciuric hypercalcemia 3	Likely benign (Apr 06, 2023)
19-46838490-G-A			Uncertain significance (Sep 08, 2023)
19-46838512-C-T			Uncertain significance (May 25, 2022)
19-46838513-G-A			Likely benign (Sep 06, 2022)
19-46838516-A-C			Likely benign (Jun 02, 2023)
19-46838519-C-T			Likely benign (Oct 16, 2023)
19-46838530-C-T		not specified	Uncertain significance (Jul 31, 2024)
19-46838532-T-C		Inborn genetic diseases	Uncertain significance (Jun 11, 2021)
19-46838540-C-T			Likely benign (Apr 26, 2020)
19-46838541-G-A			Uncertain significance (Apr 14, 2023)
19-46838542-T-A			Uncertain significance (Sep 25, 2021)
19-46838551-G-A			Uncertain significance (Dec 28, 2023)
19-46838556-A-AGGGGAGACCCTGGGGTGAGAC			Uncertain significance (Dec 11, 2021)
19-46838558-G-A			Likely benign (Nov 02, 2021)
19-46838559-G-A			Likely benign (Mar 10, 2023)
19-46838570-G-A		not specified	Likely benign (Aug 15, 2023)
19-46838578-G-A		not specified	Uncertain significance (Jul 31, 2024)
19-46838627-C-A			Likely benign (Oct 03, 2020)
19-46838692-C-T		not specified	Likely benign (Aug 15, 2023)
19-46838732-G-A		not specified • AP2S1-related disorder	Likely benign (Nov 08, 2023)
19-46838735-C-T			Uncertain significance (Sep 04, 2022)
19-46838764-C-T			Likely benign (Oct 27, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
AP2S1	protein_coding	protein_coding	ENST00000263270	5	12857

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.785	0.214	125745	0	1	125746	0.00000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.86	15	92.4	0.162	0.00000615	942
Missense in Polyphen		0	36.11	0		432
Synonymous	0.0582	39	39.5	0.988	0.00000270	261
Loss of Function	2.55	1	9.44	0.106	5.72e-7	93

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00000879	0.00000879
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: 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 (By similarity). May also play a role in extracellular calcium homeostasis. {ECO:0000250, ECO:0000269|PubMed:14745134, ECO:0000269|PubMed:15473838, ECO:0000269|PubMed:19033387, ECO:0000269|PubMed:23222959}.
• Disease: DISEASE: 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. {ECO:0000269|PubMed:23222959, ECO:0000269|PubMed:24081735}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Synaptic vesicle cycle - Homo sapiens (human);Endocytosis - Homo sapiens (human);Huntington,s disease - Homo sapiens (human);Endocrine and other factor-regulated calcium reabsorption - Homo sapiens (human);Synaptic Vesicle Pathway;GABA receptor Signaling;EGF-EGFR Signaling Pathway;Developmental Biology;Disease;Signaling by WNT;Signal Transduction;Recycling pathway of L1;Vesicle-mediated transport;Membrane Trafficking;Host Interactions of HIV factors;HIV Infection;MHC class II antigen presentation;Infectious disease;Immune System;LDL clearance;VLDLR internalisation and degradation;Plasma lipoprotein clearance;Adaptive Immune System;Retrograde neurotrophin signalling;Transport of small molecules;Neuronal System;Clathrin-mediated endocytosis;Signaling by NTRK1 (TRKA);WNT5A-dependent internalization of FZD4;PCP/CE pathway;Signaling by NTRKs;EGFR1;Beta-catenin independent WNT signaling;Nef Mediated CD4 Down-regulation;Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters;The role of Nef in HIV-1 replication and disease pathogenesis;Plasma lipoprotein assembly, remodeling, and clearance;Cargo recognition for clathrin-mediated endocytosis;Trafficking of GluR2-containing AMPA receptors;Trafficking of AMPA receptors;L1CAM interactions;Glutamate binding, activation of AMPA receptors and synaptic plasticity;Neurotransmitter receptors and postsynaptic signal transmission;Transmission across Chemical Synapses;Axon guidance;Signaling by Receptor Tyrosine Kinases;Nef Mediated CD8 Down-regulation (Consensus)

Recessive Scores

• pRec: 0.163

Intolerance Scores

• loftool: 0.186
• rvis_EVS: 0.01
• rvis_percentile_EVS: 54.63

Haploinsufficiency Scores

• pHI: 0.219
• hipred: Y
• hipred_score: 0.775
• ghis: 0.527

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.965

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Low	Low	Low
Primary Immunodeficiency	Low	Low	Low
Cancer	Low	Low	Low

Mouse Genome Informatics

• Gene name: Ap2s1

Gene ontology

• Biological process: intracellular protein transport;antigen processing and presentation of exogenous peptide antigen via MHC class II;regulation of endocytosis;low-density lipoprotein particle receptor catabolic process;low-density lipoprotein particle clearance;ephrin receptor signaling pathway;clathrin coat assembly;regulation of defense response to virus by virus;Wnt signaling pathway, planar cell polarity pathway;membrane organization;clathrin-dependent endocytosis
• Cellular component: cytosol;plasma membrane;AP-2 adaptor complex;endocytic vesicle membrane;clathrin-coated endocytic vesicle membrane;endolysosome membrane;clathrin-coated endocytic vesicle
• Molecular function: transporter activity;protein binding;protein transporter activity;clathrin adaptor activity