PIK3R2 (O00459) variants and mutations
PIK3R2 (also known as O00459) is a human protein-coding gene encoding a phosphatidylinositol 3-kinase regulatory subunit beta protein. Its annotated function is regulatory subunit of phosphoinositide-3-kinase (PI3K), a kinase that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH…. This analysis covers 2,087 PIK3R2 variants and mutations. Of these, 59% have computational variant effect predictions. Disease context includes Megalencephaly - polymicrogyria - postaxial polydactyly - hydrocephalus, megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1, and cancer. Example PIK3R2 variants include A2E, A2T, and A2V.
Variant analysis overview
- Gene: PIK3R2
- Protein: O00459
- UniProt accession: O00459
- Organism: Homo sapiens
- Variants analyzed: 2087
- Variant scope: all variants
- Completed: 2026-08-28
Variant and mutation evidence
- Variant composition: 1,798 unspecified-consequence records; 150 missense variants; 109 synonymous variants; 8 stop-gained variants; 3 in-frame deletions; 16 frameshift variants; 1 splice-region variants; 3 substitution
- Prediction scores: 1,230 variants have prediction scores (59% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: Megalencephaly - polymicrogyria - postaxial polydactyly - hydrocephalus, megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1, cancer, megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome, overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR p, Seizure, breast cancer, hereditary disease, non-small cell lung carcinoma, neurodegenerative disease, Alzheimer disease, multiple sclerosis.
Protein structure and variant hotspots
- Protein features: 4 domains; 3 post-translational modification sites.
- Structural context: 1,398 variants have structural context.
- PTM context: 8 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, ClinGen, MaveDB, LitVar.
Notable PIK3R2 variants
Examples include A2E, A2T, A2V, A2S, A2G, A2A, G3A, G3C. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- A2E (p.Ala2Glu), TOPMed rs978235304, gnomAD rs978235304, REVEL 0.14, CADD 24.30
- A2T (p.Ala2Thr), NCI-TCGA TCGA novel, REVEL 0.17, CADD 23.70, Variant assessed as somatic; moderate impact.
- A2V (p.Ala2Val), TOPMed rs978235304, gnomAD rs978235304, REVEL 0.12, CADD 23.40
- A2S (p.Ala2Ser), gnomAD 19-18155883-G-T, REVEL 0.09, CADD 23.10
- A2G (p.Ala2Gly), gnomAD 19-18155884-C-G, REVEL 0.06, CADD 21.80
- A2A (p.Ala2Ala), gnomAD 19-18155885-G-T, CADD 5.05
- G3A (p.Gly3Ala), Ensembl rs2147944561
- G3C (p.Gly3Cys), gnomAD 19-18155886-G-T, REVEL 0.10, CADD 24.20
- G3S (p.Gly3Ser), gnomAD 19-18155886-G-A, REVEL 0.05, CADD 17.20
- G3V (p.Gly3Val), gnomAD 19-18155887-G-T, REVEL 0.09, CADD 23.50
- G3D (p.Gly3Asp), gnomAD 19-18155887-G-A, REVEL 0.10, CADD 23.60
- G3G (p.Gly3Gly), rs777038649, gnomAD 19-18155888-C-T, CADD 2.87
- P4S (p.Pro4Ser), rs142933317, ClinGen CA9306628, cosmic curated COSV53227, ClinVar RCV001817052, REVEL 0.01, CADD 6.57, Benign, not specified; Megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus
- P4T (p.Pro4Thr), gnomAD 19-18155889-C-A, REVEL 0.03, CADD 4.14
- P4H (p.Pro4His), gnomAD 19-18155890-C-A, REVEL 0.09, CADD 19.90
- P4P (p.Pro4Pro), gnomAD 19-18155891-T-C, CADD 3.71
- E5G (p.Glu5Gly), Ensembl rs2147944573, REVEL 0.20, CADD 25.30
- E5* (p.Glu5Ter), gnomAD 19-18155892-G-T, CADD 40.00
- E5K (p.Glu5Lys), gnomAD 19-18155892-G-A, REVEL 0.19, CADD 25.30
- E5V (p.Glu5Val), gnomAD 19-18155893-A-T, REVEL 0.24, CADD 25.30
- E5D (p.Glu5Asp), gnomAD 19-18155894-G-T, REVEL 0.06, CADD 13.40
- E5E (p.Glu5Glu), gnomAD 19-18155894-G-A, CADD 7.28
- G6D (p.Gly6Asp), gnomAD rs1293153070, REVEL 0.24, CADD 24.60
- G6S (p.Gly6Ser), gnomAD rs2043672395, REVEL 0.19, CADD 24.00
- G6C (p.Gly6Cys), gnomAD 19-18155895-G-T, REVEL 0.23, CADD 27.40
- G6V (p.Gly6Val), gnomAD 19-18155896-G-T, REVEL 0.23, CADD 24.40
- G6G (p.Gly6Gly), gnomAD 19-18155897-C-T, CADD 12.60
- F7L (p.Phe7Leu), gnomAD 19-18155900-C-A, REVEL 0.15, CADD 22.10
- F7F (p.Phe7Phe), rs1392617246, gnomAD 19-18155900-C-T, CADD 13.20
- Q8* (p.Gln8Ter), Ensembl rs2043672496, CADD 38.00
- Q8R (p.Gln8Arg), gnomAD rs1438381426, REVEL 0.28, CADD 24.30
- Q8K (p.Gln8Lys), gnomAD 19-18155901-C-A, REVEL 0.08, CADD 23.20
- Q8E (p.Gln8Glu), gnomAD 19-18155901-C-G, REVEL 0.13, CADD 23.20
- Q8L (p.Gln8Leu), gnomAD 19-18155902-A-T, REVEL 0.28, CADD 27.90
- Q8H (p.Gln8His), gnomAD 19-18155903-G-T, REVEL 0.15, CADD 23.30
- Q8Q (p.Gln8Gln), gnomAD 19-18155903-G-A, CADD 7.63
- Y9S (p.Tyr9Ser), Ensembl rs2147944589
- Y9N (p.Tyr9Asn), gnomAD 19-18155904-T-A, REVEL 0.44, CADD 29.40
- Y9H (p.Tyr9His), gnomAD 19-18155904-T-C, REVEL 0.33, CADD 29.30
- Y9F (p.Tyr9Phe), gnomAD 19-18155905-A-T, REVEL 0.30, CADD 27.20
- Y9C (p.Tyr9Cys), gnomAD 19-18155905-A-G, REVEL 0.52, CADD 29.90
- Y9Y (p.Tyr9Tyr), rs1207377931, gnomAD 19-18155906-C-T, CADD 10.10
- Y9* (p.Tyr9Ter), gnomAD 19-18155906-C-A, CADD 37.00
- R10C (p.Arg10Cys), ExAC rs765334654, TOPMed rs765334654, gnomAD rs765334654, REVEL 0.26, CADD 26.10
- R10H (p.Arg10His), rs1371555508, ClinGen CA404799897, ClinVar RCV001335228, ClinVar RCV005465452, REVEL 0.24, CADD 28.30, Uncertain significance, Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1; Inborn genet
- R10P (p.Arg10Pro), TOPMed rs1371555508, gnomAD rs1371555508, REVEL 0.29, CADD 29.10, Uncertain significance
- R10S (p.Arg10Ser), gnomAD 19-18155907-C-A, REVEL 0.20, CADD 24.50
- R10L (p.Arg10Leu), gnomAD 19-18155908-G-T, REVEL 0.19, CADD 24.70
- R10R (p.Arg10Arg), gnomAD 19-18155909-C-A, CADD 1.07
- A11S (p.Ala11Ser), rs751392338, ClinGen CA9306631, ClinVar RCV006562814, ExAC rs751392338, REVEL 0.31, CADD 26.10, Uncertain significance, Megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome
- A11T (p.Ala11Thr), ExAC rs751392338, gnomAD rs751392338, REVEL 0.33, CADD 27.30, Uncertain significance
- A11D (p.Ala11Asp), gnomAD 19-18155911-C-A, REVEL 0.41, CADD 26.00
- A11V (p.Ala11Val), gnomAD 19-18155911-C-T, REVEL 0.27, CADD 26.00
- A11A (p.Ala11Ala), rs1360774955, gnomAD 19-18155912-T-C, CADD 3.46
- L12M (p.Leu12Met), gnomAD rs1308748759, REVEL 0.07, CADD 22.60, Uncertain significance
- L12V (p.Leu12Val), rs1308748759, ClinGen CA404799912, cosmic curated COSV53221, ClinVar RCV003277211, REVEL 0.06, CADD 18.00, Uncertain significance, Inborn genetic diseases
- p.Leu12 Tyr13del, rs2043672894, gnomAD 19-18155912-TCTGT, CADD 20.70
- L12L (p.Leu12Leu), gnomAD 19-18155913-C-T, CADD 8.69
- L12P (p.Leu12Pro), gnomAD 19-18155914-T-C, REVEL 0.29, CADD 28.40
- Y13* (p.Tyr13Ter), Ensembl rs2147944628, CADD 36.00
- Y13S (p.Tyr13Ser), Ensembl rs1599961089
- Y13P (p.Tyr13Pro), gnomAD 19-18155913-CTG-C, CADD 29.60
- Y13H (p.Tyr13His), gnomAD 19-18155916-T-C, REVEL 0.11, CADD 23.10
- Y13C (p.Tyr13Cys), gnomAD 19-18155917-A-G, REVEL 0.31, CADD 27.40
- Y13Y (p.Tyr13Tyr), gnomAD 19-18155918-C-T, CADD 10.80
- P14L (p.Pro14Leu), cosmic curated COSV53224, ExAC rs756943808, TOPMed rs756943808, gnomAD rs756943808, REVEL 0.12, CADD 19.70
- P14Q (p.Pro14Gln), ExAC rs756943808, TOPMed rs756943808, gnomAD rs756943808, REVEL 0.02, CADD 17.70
- P14S (p.Pro14Ser), cosmic curated COSV53222, Ensembl rs2147944631, REVEL 0.03, CADD 20.70
- P14T (p.Pro14Thr), Ensembl rs2147944631, REVEL 0.02, CADD 20.40
- P14P (p.Pro14Pro), rs767495472, gnomAD 19-18155921-G-A, CADD 1.77
- F15I (p.Phe15Ile), Ensembl rs2147944643, REVEL 0.26, CADD 24.80
- F15L (p.Phe15Leu), Ensembl rs2147944650, REVEL 0.21, CADD 24.90
- F15S (p.Phe15Ser), TOPMed rs2043673127
- F15V (p.Phe15Val), NCI-TCGA Cosmic COSV9944, cosmic curated COSV99444, Ensembl rs2147944643, Variant assessed as somatic; moderate impact.
- F15F (p.Phe15Phe), rs2147944650, gnomAD 19-18155924-C-T, CADD 11.80
- R16C (p.Arg16Cys), rs80233027, ClinGen CA9306634, ClinVar RCV002562292, ClinVar RCV006469166, REVEL 0.08, CADD 24.00, Conflicting interpretations, Megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome; Inbo
- R16G (p.Arg16Gly), rs80233027, ClinGen CA306163886, ClinVar RCV004953613, ClinVar RCV006564200, REVEL 0.08, CADD 23.10, Uncertain significance, Inborn genetic diseases; Megalencephaly-polymicrogyria-postaxial polydactyly-hyd
- R16H (p.Arg16His), cosmic curated COSV53225, gnomAD rs1215895377, REVEL 0.04, CADD 22.80
- R16L (p.Arg16Leu), gnomAD rs1215895377, REVEL 0.04, CADD 23.70
- R16P (p.Arg16Pro), gnomAD rs1215895377
- R16S (p.Arg16Ser), 1000Genomes rs80233027, ExAC rs80233027, TOPMed rs80233027, gnomAD rs80233027, REVEL 0.03, CADD 23.00, Benign
- R16R (p.Arg16Arg), rs1254021482, gnomAD 19-18155927-C-T, CADD 13.30
- R17G (p.Arg17Gly), gnomAD rs868385898
- R17L (p.Arg17Leu), ExAC rs755680940, TOPMed rs755680940, gnomAD rs755680940, REVEL 0.17, CADD 24.80
- R17P (p.Arg17Pro), ExAC rs755680940, TOPMed rs755680940, gnomAD rs755680940, REVEL 0.23, CADD 25.30
- R17Q (p.Arg17Gln), ExAC rs755680940, TOPMed rs755680940, gnomAD rs755680940, REVEL 0.17, CADD 25.00
- R17W (p.Arg17Trp), rs868385898, NCI-TCGA Cosmic COSV5321, cosmic curated COSV53217, gnomAD rs868385898, REVEL 0.16, CADD 29.70, Variant assessed as somatic; moderate impact.
- R17R (p.Arg17Arg), rs868385898, gnomAD 19-18155928-C-A, CADD 14.40
- E18K (p.Glu18Lys), TOPMed rs1437113802, gnomAD rs1437113802, REVEL 0.26, CADD 29.30
- E18* (p.Glu18Ter), gnomAD 19-18155931-G-T, CADD 39.00
- E18G (p.Glu18Gly), gnomAD 19-18155932-A-G, REVEL 0.22, CADD 29.90
- E18D (p.Glu18Asp), gnomAD 19-18155933-G-C, REVEL 0.04, CADD 20.10
- R19G (p.Arg19Gly), ExAC rs779519249, TOPMed rs779519249, gnomAD rs779519249, REVEL 0.11, CADD 25.80, Likely benign
- R19P (p.Arg19Pro), ExAC rs754693011, TOPMed rs754693011, gnomAD rs754693011, Uncertain significance
- R19Q (p.Arg19Gln), rs754693011, ClinGen CA9306638, cosmic curated COSV53218, ClinVar RCV006609081, REVEL 0.05, CADD 23.50, Uncertain significance, Megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome
- R19W (p.Arg19Trp), rs779519249, ClinGen CA9306637, ClinVar RCV006611189, ExAC rs779519249, REVEL 0.12, CADD 27.80, Likely benign, Megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome
- R19R (p.Arg19Arg), rs779519249, gnomAD 19-18155934-C-A, CADD 13.50
- R19L (p.Arg19Leu), gnomAD 19-18155935-G-T, REVEL 0.14, CADD 28.20
- P20A (p.Pro20Ala), gnomAD rs1164201290
- P20L (p.Pro20Leu), rs929809973, ClinGen CA306163901, cosmic curated COSV53227, ClinVar RCV004651567, REVEL 0.13, CADD 24.10, Uncertain significance, Megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome; Inbo
- P20S (p.Pro20Ser), gnomAD rs1164201290, REVEL 0.12, CADD 22.40
- P20T (p.Pro20Thr), gnomAD 19-18155937-C-A, REVEL 0.09, CADD 22.30
- P20Q (p.Pro20Gln), gnomAD 19-18155938-C-A, REVEL 0.10, CADD 22.80
- P20P (p.Pro20Pro), rs778383604, gnomAD 19-18155939-G-C, CADD 2.15
- E21G (p.Glu21Gly), Ensembl rs2147944713, REVEL 0.31, CADD 32.00
- E21Q (p.Glu21Gln), Ensembl rs1038013455
- E21V (p.Glu21Val), Ensembl rs2147944713, REVEL 0.31, CADD 31.00
- E21R (p.Glu21Arg), gnomAD 19-18155938-CG-C, CADD 9.19
- E21K (p.Glu21Lys), gnomAD 19-18155940-G-A, REVEL 0.26, CADD 31.00
- E21* (p.Glu21Ter), gnomAD 19-18155940-G-T, CADD 39.00
- E21E (p.Glu21Glu), rs2147944717, gnomAD 19-18155942-G-A, CADD 9.94
- E21D (p.Glu21Asp), gnomAD 19-18155942-G-T, REVEL 0.12, CADD 23.70
- D22A (p.Asp22Ala), Ensembl rs2147944721
- D22E (p.Asp22Glu), Ensembl rs2147944729, REVEL 0.20, CADD 24.70
- D22G (p.Asp22Gly), Ensembl rs2147944721
- D22N (p.Asp22Asn), TOPMed rs1427473626, gnomAD rs1427473626, REVEL 0.30, CADD 32.00
- D22V (p.Asp22Val), Ensembl rs2147944721, REVEL 0.50, CADD 31.00
- D22Y (p.Asp22Tyr), gnomAD 19-18155943-G-T, REVEL 0.55, CADD 32.00
- D22D (p.Asp22Asp), rs2147944729, gnomAD 19-18155945-C-T, CADD 12.60
- L23M (p.Leu23Met), cosmic curated COSV53224, Ensembl rs2147944730, REVEL 0.14, CADD 25.10
- L23L (p.Leu23Leu), gnomAD 19-18155946-C-T, CADD 13.40
- L23Q (p.Leu23Gln), gnomAD 19-18155947-T-A, REVEL 0.34, CADD 30.00
- L23P (p.Leu23Pro), gnomAD 19-18155947-T-C, REVEL 0.42, CADD 31.00
- E24G (p.Glu24Gly), Ensembl rs2147944739
- E24Q (p.Glu24Gln), TOPMed rs2043673802
- E24V (p.Glu24Val), Ensembl rs2147944739, REVEL 0.22, CADD 26.00
- E24S (p.Glu24Ser), gnomAD 19-18155947-TG-T, CADD 24.80
- E24K (p.Glu24Lys), gnomAD 19-18155949-G-A, REVEL 0.22, CADD 25.70
- E24* (p.Glu24Ter), gnomAD 19-18155949-G-T, CADD 39.00
- E24D (p.Glu24Asp), gnomAD 19-18155951-G-T, REVEL 0.21, CADD 15.70
- E24E (p.Glu24Glu), rs918341800, gnomAD 19-18155951-G-A, CADD 11.70
- L25M (p.Leu25Met), gnomAD rs1369620029, REVEL 0.26, CADD 26.70
- L25P (p.Leu25Pro), Ensembl rs2147944754
- L25Q (p.Leu25Gln), Ensembl rs2147944754
- L25R (p.Leu25Arg), Ensembl rs2147944754
- L25V (p.Leu25Val), gnomAD rs1369620029
- L25L (p.Leu25Leu), rs1429853215, gnomAD 19-18155954-G-T, CADD 8.35
- L26P (p.Leu26Pro), ExAC rs772316015, gnomAD rs772316015, REVEL 0.08, CADD 23.40
- L26Q (p.Leu26Gln), ExAC rs772316015, gnomAD rs772316015, REVEL 0.07, CADD 22.90
- L26R (p.Leu26Arg), ExAC rs772316015, gnomAD rs772316015
- L26V (p.Leu26Val), Ensembl rs2147944760
- L26M (p.Leu26Met), gnomAD 19-18155955-C-A, REVEL 0.02, CADD 19.30
- L26L (p.Leu26Leu), rs2147944760, gnomAD 19-18155955-C-T, CADD 11.90
- P27L (p.Pro27Leu), cosmic curated COSV53218, ExAC rs778478327, gnomAD rs778478327, REVEL 0.14, CADD 23.00
- P27R (p.Pro27Arg), ExAC rs778478327, gnomAD rs778478327, REVEL 0.16, CADD 25.70
- P27T (p.Pro27Thr), Ensembl rs2147944767, REVEL 0.14, CADD 23.60
- P27S (p.Pro27Ser), gnomAD 19-18155958-C-T, REVEL 0.13, CADD 25.20
- P27H (p.Pro27His), gnomAD 19-18155959-C-A, REVEL 0.17, CADD 26.00
- P27P (p.Pro27Pro), rs1292165685, gnomAD 19-18155960-C-T, CADD 1.44
- G28A (p.Gly28Ala), Ensembl rs2147944778
- G28D (p.Gly28Asp), Ensembl rs2147944778, REVEL 0.33, CADD 24.80
- G28S (p.Gly28Ser), rs112165780, ClinGen CA306163915, ClinVar RCV002560391, ClinVar RCV006468427, REVEL 0.40, CADD 29.90, Uncertain significance, Inborn genetic diseases; Megalencephaly-polymicrogyria-postaxial polydactyly-hyd
- G28C (p.Gly28Cys), gnomAD 19-18155961-G-T, REVEL 0.51, CADD 32.00
- G28V (p.Gly28Val), gnomAD 19-18155962-G-T, REVEL 0.46, CADD 29.00
- G28G (p.Gly28Gly), rs549827935, gnomAD 19-18155963-C-T, CADD 3.17
- D29A (p.Asp29Ala), Ensembl rs2147944784
- D29E (p.Asp29Glu), ExAC rs771172565, TOPMed rs771172565, gnomAD rs771172565, REVEL 0.21, CADD 18.60, Likely benign
- D29G (p.Asp29Gly), Ensembl rs2147944784
- D29N (p.Asp29Asn), Ensembl rs1599961327, REVEL 0.35, CADD 32.00
- D29V (p.Asp29Val), Ensembl rs2147944784
- D29Y (p.Asp29Tyr), gnomAD 19-18155964-G-T, REVEL 0.54, CADD 31.00
- D29D (p.Asp29Asp), rs771172565, gnomAD 19-18155966-C-T, CADD 6.68
- V30M (p.Val30Met), ExAC rs776879214, gnomAD rs776879214, REVEL 0.04, CADD 10.20
- V30L (p.Val30Leu), gnomAD 19-18155967-G-T, REVEL 0.05, CADD 6.57
- V30G (p.Val30Gly), gnomAD 19-18155968-T-G, REVEL 0.19, CADD 24.20
- V30V (p.Val30Val), rs2147944797, gnomAD 19-18155969-G-A, CADD 10.30
- L31Q (p.Leu31Gln), Ensembl rs2147944804, REVEL 0.41, CADD 32.00
- L31V (p.Leu31Val), ExAC rs759484199, TOPMed rs759484199, gnomAD rs759484199
- L31M (p.Leu31Met), gnomAD 19-18155970-C-A, REVEL 0.16, CADD 24.30
- L31L (p.Leu31Leu), rs759484199, gnomAD 19-18155970-C-T, CADD 11.80
- L31P (p.Leu31Pro), gnomAD 19-18155971-T-C, REVEL 0.54, CADD 32.00
- V32E (p.Val32Glu), Ensembl rs2147944814
- V32G (p.Val32Gly), Ensembl rs2147944814
- V32I (p.Val32Ile), Ensembl rs2147944811, REVEL 0.05, CADD 22.60
- V32L (p.Val32Leu), Ensembl rs2147944811, REVEL 0.05, CADD 22.40
- V32V (p.Val32Val), gnomAD 19-18155975-A-T, CADD 12.40
- V33E (p.Val33Glu), gnomAD rs1486498706
- V33L (p.Val33Leu), Ensembl rs2147944821, REVEL 0.22, CADD 28.60
- V33M (p.Val33Met), Ensembl rs2147944821, REVEL 0.36, CADD 30.00
- V33A (p.Val33Ala), gnomAD 19-18155977-T-C, REVEL 0.27, CADD 29.10
Public PIK3R2 analysis runs
- PIK3R2 analysis run — PIK3R2 (2,087 variants) — completed 2026-08-28