GeneBe

PRKAA2

protein-coding

protein kinase AMP-activated catalytic subunit alpha 2, the group of Protein kinase AMP-activated catalytic subunit alphas

Gene summary

The protein encoded by this gene is a catalytic subunit of the AMP-activated protein kinase (AMPK). AMPK is a heterotrimer consisting of an alpha catalytic subunit, and non-catalytic beta and gamma subunits. AMPK is an important energy-sensing enzyme that monitors cellular energy status. In response to cellular metabolic stresses, AMPK is activated, and thus phosphorylates and inactivates acetyl-CoA carboxylase (ACC) and beta-hydroxy beta-methylglutaryl-CoA reductase (HMGCR), key enzymes involved in regulating de novo biosynthesis of fatty acid and cholesterol. Studies of the mouse counterpart suggest that this catalytic subunit may control whole-body insulin sensitivity and is necessary for maintaining myocardial energy homeostasis during ischemia. [provided by RefSeq, Jul 2008]

Previous symbols:
  • PRKAA

MANE transcript

NM_006252.4

Inheritance

—

ClinVar variants

U:61B:6

Top phenotype

PRKAA2-related disorder

gnomAD constraint

pLI —, LoF o/e 0.61

Max pathogenic AF

—

Genomic locus

chr1:56,645,314-56,715,335

External References & Databases

Ensembl (ENSG00000162409)NCBI Gene (5563)OMIM (600497)HGNC:9377GenCCUniProt (P54646)AlphaFoldClinVar (PRKAA2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~70.0 kb
Loading mutation effect viewer...

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 PRKAA2 variants in ClinVar

4 Conditions Cataloged
not specifiedTotal: 53
not providedTotal: 7
PRKAA2-related disorderTotal: 5
High myopiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006252.4. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
2
clinvar
2
clinvar
 5
missense
57
clinvar
2
clinvar
 59
nonsense
2
clinvar
 2
start loss
0
frameshift
1
clinvar
 1
splice donor/acceptor (+/-2bp)
0
Total00614267
Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_006252.4RefSeqNP_006243.29MANE Select
ENST00000371244.9EnsemblENSP00000360290.49MANE Select
ENST00000860136.1EnsemblENSP00000530195.19Standard
ENST00000860136.2EnsemblENSP00000530195.19Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • PI3K-Akt signaling pathway - Homo sapiens (human)
  • mTOR signaling pathway - Homo sapiens (human)
  • Oxytocin signaling pathway - Homo sapiens (human)
  • Adipocytokine signaling pathway - Homo sapiens (human)
  • Circadian rhythm - Homo sapiens (human)

Biological Process

  • protein phosphorylation
  • fatty acid biosynthetic process
  • cholesterol biosynthetic process
  • cell cycle arrest
  • signal transduction

Molecular Function

  • chromatin binding
  • protein kinase activity
  • protein serine/threonine kinase activity
  • AMP-activated protein kinase activity
  • protein serine/threonine/tyrosine kinase activity

Cellular Component

  • nucleus
  • nucleoplasm
  • cytoplasm
  • Golgi apparatus
  • cytosol

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000371244
Coding exons
9
Length
70014
Individuals with no LoFs
125700
Homozygous LoFs
0
Heterozygous LoFs
48
Defined
125748
p
0.000191
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.992073040.6800.00001593637
Missense (PolyPhen)60132.120.454141545
Synonymous0.587971050.9270.000005431039
Loss of Function1.881626.40.6060.00000163306

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000320.00031rare
Latino/Admixed American0.000170.00017rare
Ashkenazi Jewish00.0absent
East Asian0.000160.00016rare
Finnish00.0absent
European (Non-Finnish)0.000240.00024rare
South Asian0.000230.00023rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Regulates lipid synthesis by phosphorylating and inactivating lipid metabolic enzymes such as ACACA, ACACB, GYS1, HMGCR and LIPE; regulates fatty acid and cholesterol synthesis by phosphorylating acetyl-CoA carboxylase (ACACA and ACACB) and hormone-sensitive lipase (LIPE) enzymes, respectively. Regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3. Involved in insulin receptor/INSR internalization (PubMed:25687571). AMPK stimulates glucose uptake in muscle by increasing the translocation of the glucose transporter SLC2A4/GLUT4 to the plasma membrane, possibly by mediating phosphorylation of TBC1D4/AS160. Regulates transcription and chromatin structure by phosphorylating transcription regulators involved in energy metabolism such as CRTC2/TORC2, FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP, EP300, HNF4A, p53/TP53, SREBF1, SREBF2 and PPARGC1A. Acts as a key regulator of glucose homeostasis in liver by phosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm. In response to stress, phosphorylates 'Ser-36' of histone H2B (H2BS36ph), leading to promote transcription. Acts as a key regulator of cell growth and proliferation by phosphorylating TSC2, RPTOR and ATG1/ULK1: in response to nutrient limitation, negatively regulates the mTORC1 complex by phosphorylating RPTOR component of the mTORC1 complex and by phosphorylating and activating TSC2. In response to nutrient limitation, promotes autophagy by phosphorylating and activating ATG1/ULK1. AMPK also acts as a regulator of circadian rhythm by mediating phosphorylation of CRY1, leading to destabilize it. May regulate the Wnt signaling pathway by phosphorylating CTNNB1, leading to stabilize it. Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1. Plays an important role in the differential regulation of pro-autophagy (composed of PIK3C3, BECN1, PIK3R4 and UVRAG or ATG14) and non-autophagy (composed of PIK3C3, BECN1 and PIK3R4) complexes, in response to glucose starvation. Can inhibit the non-autophagy complex by phosphorylating PIK3C3 and can activate the pro-autophagy complex by phosphorylating BECN1 (By similarity). {ECO:0000250|UniProtKB:Q8BRK8, ECO:0000269|PubMed:11518699, ECO:0000269|PubMed:11554766, ECO:0000269|PubMed:12519745, ECO:0000269|PubMed:14651849, ECO:0000269|PubMed:15866171, ECO:0000269|PubMed:17486097, ECO:0000269|PubMed:17711846, ECO:0000269|PubMed:18184930, ECO:0000269|PubMed:20074060, ECO:0000269|PubMed:20160076, ECO:0000269|PubMed:21205641, ECO:0000269|PubMed:25687571, ECO:0000269|PubMed:7959015}.;

Recessive Scores

pRec
0.230

Intolerance Scores

LoFtool
0.774
RVIS EVS
-0.67
RVIS percentile EVS
15.62

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.984

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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