PRKAA2 (P54646) variants and mutations
PRKAA2 (also known as P54646) is a human protein-coding gene encoding a 5'-AMP-activated protein kinase catalytic subunit alpha-2 protein. It contributes AMPK catalytic activity in energy-demanding tissues such as heart and skeletal muscle, linking cellular AMP or ADP levels to metabolic adaptation. Altered signaling affects glucose and lipid metabolism and stress tolerance, with limited established monogenic disease. This analysis covers 834 PRKAA2 variants and mutations. Of these, 91% have computational variant effect predictions. Disease context includes cardiovascular disorder, allergic rhinitis, and neurodegenerative disease. Example PRKAA2 variants include A2V, A2S, and A2T.
Variant analysis overview
- Gene: PRKAA2
- Protein: P54646
- UniProt accession: P54646
- Organism: Homo sapiens
- Variants analyzed: 834
- Variant scope: all variants
- Completed: 2026-08-20
Variant and mutation evidence
- Variant composition: 570 unspecified-consequence records; 156 missense variants; 65 synonymous variants; 14 stop-gained variants; 22 frameshift variants; 4 splice-region variants; 1 in-frame deletions; 2 substitution
- Prediction scores: 762 variants have prediction scores (91% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: cardiovascular disorder, allergic rhinitis, neurodegenerative disease, angina pectoris, ovarian neoplasm, coronary artery disorder, neoplasm, pathological myopia, cancer, obesity due to melanocortin 4 receptor deficiency, hepatocellular carcinoma, myopia.
Protein structure and variant hotspots
- Protein features: 1 domains; 2 binding sites; 4 post-translational modification sites.
- Structural context: 417 variants have structural context.
- PTM context: 5 variants overlap post-translational modification sites.
Data sources
Evidence in this analysis draws on EBI Proteins Variation, UniProt, gnomAD v4, EuropePMC, 3D Hotspot Analysis, Interaction Network Analysis, Protein Data Bank, AlphaFold DB, gnomAD constraint, Open Targets, MaveDB, LitVar.
Notable PRKAA2 variants
Examples include A2V, A2S, A2T, A2D, A2A, E3K, E3Q, E3*. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- A2V (p.Ala2Val), TOPMed rs1428540628, gnomAD rs1428540628, REVEL 0.25, MetaLR 0.24
- A2S (p.Ala2Ser), gnomAD 1-56645391-G-T, REVEL 0.16, CADD 22.50
- A2T (p.Ala2Thr), gnomAD 1-56645391-G-A, REVEL 0.20, CADD 22.60
- A2D (p.Ala2Asp), gnomAD 1-56645392-C-A, REVEL 0.36, CADD 23.80
- A2A (p.Ala2Ala), gnomAD 1-56645393-T-C, CADD 16.20
- E3K (p.Glu3Lys), NCI-TCGA TCGA novel, REVEL 0.26, MetaLR 0.22, Variant assessed as somatic; moderate impact.
- E3Q (p.Glu3Gln), gnomAD 1-56645394-G-C, REVEL 0.14, CADD 23.00
- E3* (p.Glu3Ter), gnomAD 1-56645394-G-T, CADD 39.00
- E3G (p.Glu3Gly), gnomAD 1-56645395-A-G, REVEL 0.24, CADD 25.60
- E3D (p.Glu3Asp), gnomAD 1-56645396-G-C, REVEL 0.13, CADD 22.10
- E3E (p.Glu3Glu), gnomAD 1-56645396-G-A, CADD 14.60
- K4S (p.Lys4Ser), gnomAD 1-56645396-GA-G, CADD 27.20
- K4* (p.Lys4Ter), gnomAD 1-56645397-A-T, CADD 38.00
- K4E (p.Lys4Glu), gnomAD 1-56645397-A-G, REVEL 0.09, CADD 22.90
- K4R (p.Lys4Arg), gnomAD 1-56645398-A-G, REVEL 0.12, CADD 22.90
- K4N (p.Lys4Asn), gnomAD 1-56645399-G-T, REVEL 0.08, CADD 23.60
- K4K (p.Lys4Lys), gnomAD 1-56645399-G-A, CADD 14.80
- Q5E (p.Gln5Glu), gnomAD rs1480741512, REVEL 0.11, MetaLR 0.16
- Q5H (p.Gln5His), rs1646631359, ClinGen CA340495261, ClinVar RCV004515070, REVEL 0.23, MetaLR 0.19, Uncertain significance, not specified
- Q5R (p.Gln5Arg), gnomAD rs1177666094, REVEL 0.10, MetaLR 0.10
- Q5* (p.Gln5Ter), gnomAD 1-56645400-C-T, CADD 38.00
- Q5K (p.Gln5Lys), gnomAD 1-56645400-C-A, REVEL 0.11, CADD 22.20
- Q5P (p.Gln5Pro), gnomAD 1-56645401-A-C, REVEL 0.14, CADD 22.90
- Q5L (p.Gln5Leu), gnomAD 1-56645401-A-T, REVEL 0.14, CADD 23.00
- Q5Q (p.Gln5Gln), rs1646631359, gnomAD 1-56645402-G-A, CADD 14.70
- K6* (p.Lys6Ter), gnomAD 1-56645403-A-T, CADD 39.00
- K6E (p.Lys6Glu), gnomAD 1-56645403-A-G, REVEL 0.37, CADD 23.60
- K6M (p.Lys6Met), gnomAD 1-56645404-A-T, REVEL 0.42, CADD 29.20
- K6R (p.Lys6Arg), gnomAD 1-56645404-A-G, REVEL 0.20, CADD 23.50
- K6N (p.Lys6Asn), gnomAD 1-56645405-G-C, REVEL 0.14, CADD 22.70
- K6K (p.Lys6Lys), gnomAD 1-56645405-G-A, CADD 14.60
- H7N (p.His7Asn), rs2523473692, ClinGen CA340495286, ClinVar RCV004321653, REVEL 0.20, MetaLR 0.19, Uncertain significance, not specified
- H7Q (p.His7Gln), TOPMed rs1196595450, gnomAD rs1196595450, REVEL 0.28, MetaLR 0.16, Uncertain significance, not specified
- H7Y (p.His7Tyr), gnomAD 1-56645406-C-T, REVEL 0.34, CADD 22.70
- H7R (p.His7Arg), gnomAD 1-56645407-A-G, REVEL 0.28, CADD 21.10
- H7L (p.His7Leu), gnomAD 1-56645407-A-T, REVEL 0.35, MetaLR 0.20
- H7H (p.His7His), gnomAD 1-56645408-C-T, CADD 14.50
- D8E (p.Asp8Glu), 1000Genomes rs200643979, ExAC rs200643979, gnomAD rs200643979, NCI-TCGA TCGA novel, REVEL 0.08, MetaLR 0.13, Variant assessed as somatic; moderate impact.
- D8H (p.Asp8His), gnomAD rs1235784068, REVEL 0.19, MetaLR 0.21
- D8Y (p.Asp8Tyr), gnomAD rs1235784068, REVEL 0.32, MetaLR 0.25
- D8N (p.Asp8Asn), gnomAD 1-56645409-G-A, REVEL 0.15, MetaLR 0.19
- D8G (p.Asp8Gly), gnomAD 1-56645410-A-G, REVEL 0.15, MetaLR 0.19
- D8V (p.Asp8Val), gnomAD 1-56645410-A-T, REVEL 0.24, MetaLR 0.21
- D8D (p.Asp8Asp), gnomAD 1-56645411-C-T, CADD 14.40
- G9E (p.Gly9Glu), TOPMed rs1434366087, gnomAD rs1434366087, REVEL 0.36, MetaLR 0.16
- G9V (p.Gly9Val), TOPMed rs1434366087, gnomAD rs1434366087, REVEL 0.36, MetaLR 0.20
- G9W (p.Gly9Trp), gnomAD 1-56645412-G-T, REVEL 0.55, MetaLR 0.49
- G9R (p.Gly9Arg), gnomAD 1-56645412-G-A, REVEL 0.34, MetaLR 0.21
- G9G (p.Gly9Gly), gnomAD 1-56645414-G-T, CADD 14.60
- R10W (p.Arg10Trp), NCI-TCGA TCGA novel, REVEL 0.26, MetaLR 0.22, Variant assessed as somatic; moderate impact.
- R10G (p.Arg10Gly), gnomAD 1-56645411-CG-C, CADD 29.60
- R10R (p.Arg10Arg), gnomAD 1-56645415-C-A, CADD 14.20
- R10Q (p.Arg10Gln), gnomAD 1-56645416-G-A, REVEL 0.15, MetaLR 0.15
- R10L (p.Arg10Leu), gnomAD 1-56645416-G-T, REVEL 0.25, MetaLR 0.18
- V11* (p.Val11Ter), gnomAD 1-56645415-CG-C, CADD 31.00
- V11M (p.Val11Met), gnomAD 1-56645418-G-A, REVEL 0.33, MetaLR 0.22
- V11L (p.Val11Leu), gnomAD 1-56645418-G-T, REVEL 0.19, MetaLR 0.17
- V11G (p.Val11Gly), gnomAD 1-56645419-T-G, REVEL 0.57, MetaLR 0.39
- V11A (p.Val11Ala), gnomAD 1-56645419-T-C, REVEL 0.35, MetaLR 0.29
- V11V (p.Val11Val), rs1426490355, gnomAD 1-56645420-G-A, CADD 16.30
- K12R (p.Lys12Arg), 1000Genomes rs752436954, ExAC rs752436954, TOPMed rs752436954, gnomAD rs752436954, REVEL 0.14, MetaLR 0.16
- K12E (p.Lys12Glu), gnomAD 1-56645421-A-G, REVEL 0.45, MetaLR 0.23
- K12* (p.Lys12Ter), gnomAD 1-56645421-A-T, CADD 39.00
- K12M (p.Lys12Met), gnomAD 1-56645422-A-T, REVEL 0.53, MetaLR 0.34
- K12K (p.Lys12Lys), gnomAD 1-56645423-G-A, CADD 15.00
- K12N (p.Lys12Asn), gnomAD 1-56645423-G-T, REVEL 0.37, MetaLR 0.34
- I13F (p.Ile13Phe), ExAC rs757985759, TOPMed rs757985759, gnomAD rs757985759, REVEL 0.24, MetaLR 0.08
- I13V (p.Ile13Val), ExAC rs757985759, TOPMed rs757985759, gnomAD rs757985759, REVEL 0.08, MetaLR 0.04
- I13T (p.Ile13Thr), gnomAD 1-56645425-T-C, REVEL 0.38, MetaLR 0.09
- I13I (p.Ile13Ile), gnomAD 1-56645426-C-A, CADD 15.60
- G14R (p.Gly14Arg), TOPMed rs966678434, gnomAD rs966678434, REVEL 0.47, MetaLR 0.12
- G14* (p.Gly14Ter), gnomAD 1-56645427-G-T, CADD 38.00
- G14V (p.Gly14Val), gnomAD 1-56645428-G-T, REVEL 0.49, MetaLR 0.16
- G14E (p.Gly14Glu), gnomAD 1-56645428-G-A, REVEL 0.46, MetaLR 0.10
- G14G (p.Gly14Gly), rs1462662537, gnomAD 1-56645429-A-T, CADD 12.60
- H15P (p.His15Pro), ExAC rs763759018, gnomAD rs763759018, REVEL 0.23, MetaLR 0.07
- H15Y (p.His15Tyr), rs1330973554, ClinGen CA340495421, ClinVar RCV004515073, gnomAD rs1330973554, REVEL 0.30, MetaLR 0.07, Uncertain significance, not specified
- H15N (p.His15Asn), gnomAD 1-56645430-C-A, REVEL 0.17, MetaLR 0.02
- H15R (p.His15Arg), gnomAD 1-56645431-A-G, REVEL 0.16, MetaLR 0.02
- H15L (p.His15Leu), gnomAD 1-56645431-A-T, REVEL 0.25, MetaLR 0.04
- H15Q (p.His15Gln), gnomAD 1-56645432-C-A, REVEL 0.09, MetaLR 0.03
- H15H (p.His15His), gnomAD 1-56645432-C-T, CADD 15.30
- Y16* (p.Tyr16Ter), ExAC rs751060247, TOPMed rs751060247, gnomAD rs751060247, CADD 37.00
- Y16C (p.Tyr16Cys), Ensembl rs868402020, REVEL 0.37, MetaLR 0.35
- Y16H (p.Tyr16His), gnomAD 1-56645433-T-C, REVEL 0.54, MetaLR 0.33
- Y16F (p.Tyr16Phe), gnomAD 1-56645434-A-T, REVEL 0.35, MetaLR 0.16
- Y16Y (p.Tyr16Tyr), rs751060247, gnomAD 1-56645435-C-T, CADD 15.30
- V17G (p.Val17Gly), gnomAD rs1366799809, REVEL 0.19, MetaLR 0.22
- V17M (p.Val17Met), cosmic curated COSV64804, TOPMed rs1304339883, gnomAD rs1304339883, REVEL 0.12, MetaLR 0.18, Uncertain significance, not specified
- V17L (p.Val17Leu), gnomAD 1-56645436-G-T, REVEL 0.03, MetaLR 0.10
- V17E (p.Val17Glu), gnomAD 1-56645437-T-A, REVEL 0.17, MetaLR 0.12
- V17A (p.Val17Ala), gnomAD 1-56645437-T-C, REVEL 0.08, MetaLR 0.15
- V17V (p.Val17Val), gnomAD 1-56645438-G-T, CADD 13.60
- L18V (p.Leu18Val), gnomAD 1-56645439-C-G, REVEL 0.23, MetaLR 0.06
- L18M (p.Leu18Met), gnomAD 1-56645439-C-A, REVEL 0.23, MetaLR 0.14
- L18L (p.Leu18Leu), gnomAD 1-56645439-C-T, CADD 14.90
- L18Q (p.Leu18Gln), gnomAD 1-56645440-T-A, REVEL 0.54, MetaLR 0.18
- L18P (p.Leu18Pro), gnomAD 1-56645440-T-C, REVEL 0.60, MetaLR 0.14
- G19A (p.Gly19Ala), gnomAD 1-56645440-TG-T, CADD 25.00
- G19S (p.Gly19Ser), gnomAD 1-56645442-G-A, REVEL 0.41, MetaLR 0.12
- G19C (p.Gly19Cys), gnomAD 1-56645442-G-T, REVEL 0.45, MetaLR 0.09
- G19V (p.Gly19Val), gnomAD 1-56645443-G-T, REVEL 0.45, MetaLR 0.10
- G19D (p.Gly19Asp), gnomAD 1-56645443-G-A, REVEL 0.39, MetaLR 0.13
- G19G (p.Gly19Gly), gnomAD 1-56645444-C-G, CADD 14.60
- D20N (p.Asp20Asn), ExAC rs781236377, TOPMed rs781236377, gnomAD rs781236377, REVEL 0.10, MetaLR 0.05, Uncertain significance, not specified
- D20Y (p.Asp20Tyr), gnomAD 1-56645445-G-T, REVEL 0.42, MetaLR 0.14
- D20G (p.Asp20Gly), gnomAD 1-56645446-A-G, REVEL 0.30, MetaLR 0.05
- D20E (p.Asp20Glu), gnomAD 1-56645447-C-A, REVEL 0.12, MetaLR 0.02
- D20D (p.Asp20Asp), gnomAD 1-56645447-C-T, CADD 15.80
- T21R (p.Thr21Arg), TOPMed rs1646631800, REVEL 0.44, MetaLR 0.10
- T21A (p.Thr21Ala), gnomAD 1-56645448-A-G, REVEL 0.26, MetaLR 0.09
- T21K (p.Thr21Lys), gnomAD 1-56645449-C-A, REVEL 0.33, MetaLR 0.07
- T21M (p.Thr21Met), gnomAD 1-56645449-C-T, REVEL 0.44, MetaLR 0.13
- T21T (p.Thr21Thr), gnomAD 1-56645450-G-T, CADD 14.40
- L22M (p.Leu22Met), gnomAD 1-56645451-C-A, REVEL 0.42, MetaLR 0.33
- L22L (p.Leu22Leu), gnomAD 1-56645451-C-T, CADD 15.30
- L22Q (p.Leu22Gln), gnomAD 1-56645452-T-A, REVEL 0.63, MetaLR 0.38
- L22P (p.Leu22Pro), gnomAD 1-56645452-T-C, REVEL 0.68, MetaLR 0.38
- G23C (p.Gly23Cys), gnomAD 1-56645454-G-T, REVEL 0.79, MetaLR 0.57
- G23S (p.Gly23Ser), gnomAD 1-56645454-G-A, REVEL 0.72, MetaLR 0.53
- G23V (p.Gly23Val), gnomAD 1-56645455-G-T, REVEL 0.77, MetaLR 0.61
- G23D (p.Gly23Asp), gnomAD 1-56645455-G-A, REVEL 0.74, MetaLR 0.50
- G23G (p.Gly23Gly), gnomAD 1-56645456-C-G, CADD 16.20
- V24I (p.Val24Ile), TOPMed rs1295726050, gnomAD rs1295726050, REVEL 0.25, MetaLR 0.20
- V24L (p.Val24Leu), TOPMed rs1295726050, gnomAD rs1295726050, REVEL 0.26, MetaLR 0.27
- V24F (p.Val24Phe), gnomAD 1-56645457-G-T, REVEL 0.45, MetaLR 0.35
- V24V (p.Val24Val), gnomAD 1-56645459-C-A, CADD 15.80
- G25D (p.Gly25Asp), cosmic curated COSV64802, Ensembl rs867333017, REVEL 0.90, MetaLR 0.84
- G25S (p.Gly25Ser), ExAC rs745675639, gnomAD rs745675639, REVEL 0.94, MetaLR 0.82
- G25A (p.Gly25Ala), gnomAD 1-56645458-TC-T, CADD 27.20
- G25C (p.Gly25Cys), gnomAD 1-56645460-G-T, REVEL 0.96, MetaLR 0.87
- G25R (p.Gly25Arg), gnomAD 1-56645460-G-C, REVEL 0.95, MetaLR 0.87
- G25V (p.Gly25Val), gnomAD 1-56645461-G-T, REVEL 0.92, MetaLR 0.86
- G25G (p.Gly25Gly), rs755984518, gnomAD 1-56645462-C-G, CADD 15.40
- T26N (p.Thr26Asn), TOPMed rs1236124861, gnomAD rs1236124861, REVEL 0.22, MetaLR 0.10
- T26A (p.Thr26Ala), gnomAD 1-56645463-A-G, REVEL 0.17, MetaLR 0.03
- T26S (p.Thr26Ser), gnomAD 1-56645464-C-G, REVEL 0.10, MetaLR 0.02
- T26I (p.Thr26Ile), gnomAD 1-56645464-C-T, REVEL 0.34, MetaLR 0.11
- T26T (p.Thr26Thr), gnomAD 1-56645465-C-G, CADD 15.40
- F27L (p.Phe27Leu), ExAC rs749587981, gnomAD rs749587981, REVEL 0.44, MetaLR 0.21
- F27S (p.Phe27Ser), gnomAD 1-56645465-CT-C, CADD 32.00
- F27I (p.Phe27Ile), gnomAD 1-56645466-T-A, REVEL 0.53, MetaLR 0.31
- F27Y (p.Phe27Tyr), gnomAD 1-56645467-T-A, REVEL 0.38, MetaLR 0.12
- F27F (p.Phe27Phe), rs749587981, gnomAD 1-56645468-C-T, CADD 16.10
- G28S (p.Gly28Ser), NCI-TCGA TCGA novel, REVEL 0.61, MetaLR 0.23, Variant assessed as somatic; moderate impact.
- G28C (p.Gly28Cys), gnomAD 1-56645469-G-T, REVEL 0.73, MetaLR 0.44
- G28D (p.Gly28Asp), gnomAD 1-56645470-G-A, REVEL 0.69, MetaLR 0.51
- G28V (p.Gly28Val), gnomAD 1-56645470-G-T, REVEL 0.74, MetaLR 0.48
- G28A (p.Gly28Ala), gnomAD 1-56645470-G-C, REVEL 0.55, MetaLR 0.23
- G28G (p.Gly28Gly), gnomAD 1-56645471-C-A, CADD 15.30
- K29* (p.Lys29Ter), gnomAD 1-56645472-A-T, CADD 41.00
- K29E (p.Lys29Glu), gnomAD 1-56645472-A-G, REVEL 0.43, MetaLR 0.32
- K29T (p.Lys29Thr), gnomAD 1-56645473-A-C, REVEL 0.49, MetaLR 0.26
- K29I (p.Lys29Ile), gnomAD 1-56645473-A-T, REVEL 0.53, MetaLR 0.38
- K29R (p.Lys29Arg), gnomAD 1-56645473-A-G, REVEL 0.31, MetaLR 0.21
- K29K (p.Lys29Lys), gnomAD 1-56645474-A-G, CADD 22.60
- K29N (p.Lys29Asn), gnomAD 1-56645474-A-T, REVEL 0.59, MetaLR 0.44
- V30L (p.Val30Leu), gnomAD 1-56645475-G-T, REVEL 0.56, MetaLR 0.37
- V30M (p.Val30Met), gnomAD 1-56645475-G-A, REVEL 0.59, MetaLR 0.41
- V30E (p.Val30Glu), gnomAD 1-56645476-T-A, REVEL 0.53, MetaLR 0.42
- V30A (p.Val30Ala), gnomAD 1-56645476-T-C, REVEL 0.57, MetaLR 0.42
- V30V (p.Val30Val), rs768743375, gnomAD 1-56645477-G-T, CADD 16.30
- K31R (p.Lys31Arg), gnomAD 1-56645477-GA-G, CADD 34.00
- K31* (p.Lys31Ter), gnomAD 1-56645478-A-T, CADD 41.00
- K31E (p.Lys31Glu), gnomAD 1-56645478-A-G, REVEL 0.38, MetaLR 0.11
- K31M (p.Lys31Met), gnomAD 1-56645479-A-T, REVEL 0.41, MetaLR 0.09
- K31T (p.Lys31Thr), gnomAD 1-56645479-A-C, REVEL 0.43, MetaLR 0.12
- K31N (p.Lys31Asn), gnomAD 1-56645480-G-C, REVEL 0.20, MetaLR 0.07
- K31K (p.Lys31Lys), rs1646632088, gnomAD 1-56645480-G-A, CADD 20.30
- I32V (p.Ile32Val), 1000Genomes rs774427325, ExAC rs774427325, gnomAD rs774427325, REVEL 0.06, MetaLR 0.02
- I32F (p.Ile32Phe), gnomAD 1-56645481-A-T, REVEL 0.12, MetaLR 0.04
- I32N (p.Ile32Asn), gnomAD 1-56674381-T-A, REVEL 0.29, MetaLR 0.08
- I32I (p.Ile32Ile), gnomAD 1-56674382-T-A, CADD 22.10
- G33* (p.Gly33Ter), NCI-TCGA Cosmic COSV6480, cosmic curated COSV64804, Variant assessed as somatic; high impact.
- G33R (p.Gly33Arg), gnomAD 1-56674383-G-A, REVEL 0.80, MetaLR 0.26
- G33V (p.Gly33Val), gnomAD 1-56674384-G-T, REVEL 0.72, MetaLR 0.13
- G33G (p.Gly33Gly), gnomAD 1-56674385-A-C, CADD 11.30
- E34G (p.Glu34Gly), TOPMed rs1296094303, gnomAD rs1296094303, REVEL 0.32, MetaLR 0.09
- E34* (p.Glu34Ter), gnomAD 1-56674386-G-T, CADD 38.00
- E34K (p.Glu34Lys), gnomAD 1-56674386-G-A, REVEL 0.17, MetaLR 0.03
Public PRKAA2 analysis runs
- PRKAA2 analysis run — PRKAA2 (834 variants) — completed 2026-08-20