AAK1

protein-coding

AP2 associated kinase 1, the group of Small nucleolar RNA protein coding host genes

Gene summary

This gene encodes a member of the SNF1 subfamily of serine/threonine protein kinases. Adaptor-related protein complex 2 (AP-2 complexes) functions during receptor-mediated endocytosis to trigger clathrin assembly, interact with membrane-bound receptors, and recruit encodytic accessory factors. The encoded protein interacts with and phosphorylates a subunit of the AP-2 complex, which promotes binding of AP-2 to sorting signals found in membrane-bound receptors and subsequent receptor endocytosis. Its kinase activity is stimulated by clathrin. This kinase has been shown to play an important role in regulating the clathrin-mediated endocytosis of the rabies virus, facilitating infection. Inhibitors of this kinase are being studied as candidate therapeutics to disrupt the entry of viruses, including SARS-CoV-2, into target cells. It is also involved in positive regulation of Notch pathway signaling in mammals. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Aug 2020]

MANE transcript

NM_014911.5

Inheritance

—

ClinVar variants

U:113B:8

Top phenotype

Tooth agenesis

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr2:69,457,997-69,674,349

External References & Databases

Ensembl (ENSG00000115977)

Transcript & Mutation Effects

hg38 • Region Span ~216.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AAK1 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 95

not providedTotal: 7

Tooth agenesisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014911.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	4 clinvar	1 clinvar	9
missense			101 clinvar	2 clinvar	1 clinvar	104
nonsense			1 clinvar			1
start loss			1 clinvar			1
frameshift						0
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	0	0	113	6	2	121

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014911.5	RefSeq	NP_055726.4	21	MANE Select
ENST00000409085.9	Ensembl	ENSP00000386456.3	21	MANE Select
NM_001371575.1	RefSeq	NP_001358504.1	20	Standard
NM_001371577.1	RefSeq	NP_001358506.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vesicle-mediated transport
Membrane Trafficking
Clathrin-mediated endocytosis
Cargo recognition for clathrin-mediated endocytosis

Biological Process

protein phosphorylation
endocytosis
regulation of endocytosis
regulation of protein localization
positive regulation of Notch signaling pathway

Molecular Function

protein serine/threonine kinase activity
Notch binding
protein binding
ATP binding
AP-2 adaptor complex binding

Cellular Component

nucleus
cytosol
clathrin-coated pit
extrinsic component of plasma membrane
clathrin-coated vesicle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000409085
Coding exons: 21
Length: 212950
Individuals with no LoFs: 124639
Homozygous LoFs: 0
Heterozygous LoFs: 6
Defined: 124645
p: 0.0000241

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.61	342	508	0.674	0.0000258	6227
Missense (PolyPhen)		62	100.55	0.61662		1265
Synonymous	0.334	189	195	0.970	0.0000103	1934
Loss of Function	6.20	2	48.7	0.0411	0.00000224	544

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.000037	0.000035	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Regulates clathrin-mediated endocytosis by phosphorylating the AP2M1/mu2 subunit of the adaptor protein complex 2 (AP-2) which ensures high affinity binding of AP-2 to cargo membrane proteins during the initial stages of endocytosis. Isoform 1 and isoform 2 display similar levels of kinase activity towards AP2M1. Regulates phosphorylation of other AP-2 subunits as well as AP-2 localization and AP-2-mediated internalization of ligand complexes. Phosphorylates NUMB and regulates its cellular localization, promoting NUMB localization to endosomes. Binds to and stabilizes the activated form of NOTCH1, increases its localization in endosomes and regulates its transcriptional activity. {ECO:0000269|PubMed:12952931, ECO:0000269|PubMed:17494869, ECO:0000269|PubMed:18657069, ECO:0000269|PubMed:21464124}.;

Recessive Scores

pRec: 0.0954

Intolerance Scores

RVIS EVS: -0.66
RVIS percentile EVS: 15.91

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.446

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	High	Medium	High
Cancer	High	Medium	High