PIK3CA (P42336) variants and mutations
PIK3CA (also known as P42336) is a human protein-coding gene encoding a phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform protein. Its p110-alpha catalytic activity generates PIP3 and activates AKT-dependent growth, survival, and metabolic signaling downstream of many receptors. Activating variants are frequent cancer drivers and, when present mosaically during development, can cause PIK3CA-related overgrowth spectrum. This analysis covers 4,169 PIK3CA variants and mutations. Of these, 27% have computational variant effect predictions. Disease context includes megalencephaly-capillary malformation-polymicrogyria syndrome, CLOVE syndrome, and CLOVES syndrome. Example PIK3CA variants include M1T, P2A, and P2R.
Variant analysis overview
- Gene: PIK3CA
- Protein: P42336
- UniProt accession: P42336
- Organism: Homo sapiens
- Variants analyzed: 4169
- Variant scope: all variants
- Completed: 2026-09-20
Variant and mutation evidence
- Variant composition: 4,061 unspecified-consequence records; 45 missense variants; 107 synonymous variants; 2 in-frame deletions; 2 stop-gained variants; 5 frameshift variants; 4 splice-region variants; 3 substitution
- Prediction scores: 1,144 variants have prediction scores (27% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: megalencephaly-capillary malformation-polymicrogyria syndrome, CLOVE syndrome, CLOVES syndrome, PIK3CA-related overgrowth spectrum, breast cancer, Cowden syndrome 5, ovarian cancer, seborrheic keratosis, breast adenocarcinoma, CLAPO syndrome, pik3ca related overgrowth spectrum, Cowden disease.
Protein structure and variant hotspots
- Protein features: 5 domains.
- Structural context: 3,118 variants have structural context.
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 PIK3CA variants
Examples include M1T, P2A, P2R, P2S, P2T, P2H, P2P, P3L. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- M1T (p.Met1Thr), rs2108384932, ClinGen CA355270016, ClinVar RCV006645517, MetaLR 0.33, MetaSVM -0.29, Uncertain significance, PIK3CA related overgrowth syndrome
- P2A (p.Pro2Ala), Ensembl rs1576931853, Uncertain significance
- P2R (p.Pro2Arg), Ensembl rs2108384945
- P2S (p.Pro2Ser), rs1576931853, ClinGen CA355270070, ClinVar RCV002739093, Ensembl rs1576931853, REVEL 0.34, CADD 22.80, Uncertain significance, Inborn genetic diseases
- P2T (p.Pro2Thr), gnomAD 3-179198829-C-A, REVEL 0.42, CADD 22.60
- P2H (p.Pro2His), gnomAD 3-179198830-C-A, REVEL 0.52, CADD 23.50
- P2P (p.Pro2Pro), gnomAD 3-179198831-T-C, CADD 13.30
- P3L (p.Pro3Leu), Ensembl rs2108384948, REVEL 0.64, CADD 25.60
- P3Q (p.Pro3Gln), Ensembl rs2108384948, REVEL 0.57, CADD 25.10
- P3T (p.Pro3Thr), gnomAD 3-179198832-C-A, REVEL 0.60, CADD 24.60
- R4* (p.Arg4Ter), rs1051397, NCI-TCGA Cosmic COSV5596, cosmic curated COSV55961, TOPMed rs1051397, CADD 35.00, Variant assessed as somatic; high impact.
- R4G (p.Arg4Gly), TOPMed rs1051397, gnomAD rs1051397, REVEL 0.40, CADD 23.20
- R4L (p.Arg4Leu), ExAC rs749956691, TOPMed rs749956691, gnomAD rs749956691, REVEL 0.46, CADD 23.40, Uncertain significance
- R4P (p.Arg4Pro), rs749956691, ClinGen CA355270140, ClinVar RCV001761056, ExAC rs749956691, AlphaMissense 0.67, MetaLR 0.38, Uncertain significance, not provided
- R4Q (p.Arg4Gln), cosmic curated COSV55941, ExAC rs749956691, TOPMed rs749956691, gnomAD rs749956691, Uncertain significance
- R4R (p.Arg4Arg), rs1051397, gnomAD 3-179198835-C-A, CADD 10.50
- P5A (p.Pro5Ala), Ensembl rs2108384970
- P5L (p.Pro5Leu), cosmic curated COSV10956, Ensembl rs2108384975
- P5R (p.Pro5Arg), Ensembl rs2108384975
- P5S (p.Pro5Ser), Ensembl rs2108384970, REVEL 0.45, CADD 24.50
- P5Q (p.Pro5Gln), gnomAD 3-179198839-C-A, REVEL 0.48, CADD 25.00
- P5P (p.Pro5Pro), rs2108384979, gnomAD 3-179198840-A-G, CADD 12.30
- S6* (p.Ser6Ter), Ensembl rs2108384987, CADD 35.00
- S6L (p.Ser6Leu), cosmic curated COSV10456, Ensembl rs2108384987
- S6P (p.Ser6Pro), TOPMed rs1724333023, gnomAD rs1724333023, REVEL 0.55, CADD 26.80
- S6T (p.Ser6Thr), TOPMed rs1724333023, gnomAD rs1724333023
- S7* (p.Ser7Ter), Ensembl rs2108385000, CADD 35.00
- S7A (p.Ser7Ala), Ensembl rs2108384996, REVEL 0.37, CADD 25.70
- S7L (p.Ser7Leu), cosmic curated COSV10608, Ensembl rs2108385000, REVEL 0.51, CADD 26.20
- S7T (p.Ser7Thr), Ensembl rs2108384996
- G8A (p.Gly8Ala), cosmic curated COSV10585, NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- G8C (p.Gly8Cys), Ensembl rs2108385009, Uncertain significance
- G8D (p.Gly8Asp), cosmic curated COSV55910, Ensembl rs2108385018
- G8R (p.Gly8Arg), Ensembl rs2108385009, Uncertain significance, Inborn genetic diseases
- G8S (p.Gly8Ser), Ensembl rs2108385009, Uncertain significance
- G8V (p.Gly8Val), Ensembl rs2108385018
- E9* (p.Glu9Ter), Ensembl rs2108385031, CADD 36.00
- E9D (p.Glu9Asp), cosmic curated COSV11398, Ensembl rs2108385039
- E9Q (p.Glu9Gln), Ensembl rs2108385031, Uncertain significance, not provided
- E9V (p.Glu9Val), Ensembl rs2108385038
- E9E (p.Glu9Glu), gnomAD 3-179198852-A-G, CADD 13.20
- L10M (p.Leu10Met), Ensembl rs2108385041
- L10P (p.Leu10Pro), rs2108385050, ClinGen CA355270329, cosmic curated COSV55969, ClinVar RCV003225477, AlphaMissense 0.99, MetaLR 0.56, Uncertain significance, not provided
- L10Q (p.Leu10Gln), NCI-TCGA Cosmic COSV5587, NCI-TCGA Cosmic COSV5596, Ensembl rs2108385050, Uncertain significance
- L10V (p.Leu10Val), Ensembl rs2108385041
- L10L (p.Leu10Leu), rs758862912, gnomAD 3-179198855-G-C, CADD 9.13
- W11* (p.Trp11Ter), Ensembl rs2108385056
- W11C (p.Trp11Cys), Ensembl rs2108385069, cosmic curated COSV11399
- W11L (p.Trp11Leu), NCI-TCGA Cosmic COSV5587, cosmic curated COSV55873, NCI-TCGA Cosmic COSV5589, Ensembl rs2108385056, Variant assessed as somatic; moderate impact.
- W11S (p.Trp11Ser), NCI-TCGA Cosmic COSV5587, NCI-TCGA Cosmic COSV5589, cosmic curated COSV55891, Ensembl rs2108385056, Variant assessed as somatic; moderate impact.
- G12A (p.Gly12Ala), Ensembl rs2108385083
- G12C (p.Gly12Cys), cosmic curated COSV55908, Ensembl rs2108385075, REVEL 0.66, CADD 25.20
- G12D (p.Gly12Asp), NCI-TCGA Cosmic COSV5589, cosmic curated COSV55899, Ensembl rs2108385083, REVEL 0.58, CADD 25.90, Variant assessed as somatic; moderate impact.
- G12R (p.Gly12Arg), Ensembl rs2108385075
- G12S (p.Gly12Ser), Ensembl rs2108385075
- I13F (p.Ile13Phe), Ensembl rs2108385090, Uncertain significance
- I13N (p.Ile13Asn), Ensembl rs2108385095
- I13S (p.Ile13Ser), cosmic curated COSV10608, Ensembl rs2108385095
- I13T (p.Ile13Thr), NCI-TCGA Cosmic COSV5590, cosmic curated COSV55900, Ensembl rs2108385095, Variant assessed as somatic; moderate impact.
- I13V (p.Ile13Val), rs2108385090, ClinGen CA355270453, ClinVar RCV001964254, Ensembl rs2108385090, AlphaMissense 0.11, MetaLR 0.12, Uncertain significance, Cowden syndrome
- I13I (p.Ile13Ile), gnomAD 3-179198864-C-A, CADD 11.20
- H14D (p.His14Asp), Ensembl rs1576931874, Uncertain significance
- H14L (p.His14Leu), Ensembl rs2108385107
- H14Q (p.His14Gln), rs766833890, ExAC rs766833890, TOPMed rs766833890, gnomAD rs766833890, REVEL 0.46, CADD 22.70, Uncertain significance, Inborn genetic diseases
- H14Y (p.His14Tyr), rs1576931874, ClinGen CA355270487, cosmic curated COSV56031, ClinVar RCV000805736, REVEL 0.60, CADD 24.20, Uncertain significance, Cowden syndrome
- H14N (p.His14Asn), gnomAD 3-179198865-C-A, REVEL 0.44, CADD 22.90
- H14H (p.His14His), rs766833890, gnomAD 3-179198867-C-T, CADD 9.61
- L15F (p.Leu15Phe), rs751930632, ClinGen CA2710491, cosmic curated COSV11399, ClinVar RCV002342371, REVEL 0.32, CADD 23.90, Uncertain significance, Cowden syndrome; Inborn genetic diseases
- L15M (p.Leu15Met), Ensembl rs2108385118
- L15S (p.Leu15Ser), Ensembl rs2108385120, Uncertain significance
- L15W (p.Leu15Trp), rs2108385120, ClinGen CA355270524, ClinVar RCV002328697, AlphaMissense 0.77, MetaLR 0.37, Uncertain significance, Inborn genetic diseases
- M16K (p.Met16Lys), Ensembl rs2108385129, Uncertain significance, Inborn genetic diseases
- M16L (p.Met16Leu), Ensembl rs2108385128
- M16T (p.Met16Thr), Ensembl rs2108385129
- M16V (p.Met16Val), cosmic curated COSV55979, Ensembl rs2108385128
- M16I (p.Met16Ile), gnomAD 3-179198873-G-A, REVEL 0.47, CADD 25.60
- P17A (p.Pro17Ala), Ensembl rs2108385134
- P17H (p.Pro17His), gnomAD rs1470180843
- P17L (p.Pro17Leu), gnomAD rs1470180843
- P17R (p.Pro17Arg), gnomAD rs1470180843
- P17S (p.Pro17Ser), cosmic curated COSV55944, Ensembl rs2108385134
- P17T (p.Pro17Thr), Ensembl rs2108385134, REVEL 0.53, CADD 24.60
- P18A (p.Pro18Ala), TOPMed rs1178810605, gnomAD rs1178810605, Uncertain significance
- P18L (p.Pro18Leu), cosmic curated COSV55879, Ensembl rs2108385148
- P18Q (p.Pro18Gln), Ensembl rs2108385148
- P18R (p.Pro18Arg), Ensembl rs2108385148
- P18S (p.Pro18Ser), rs1178810605, ClinGen CA355270638, ClinVar RCV003311394, TOPMed rs1178810605, REVEL 0.36, CADD 19.00, Uncertain significance, Inborn genetic diseases
- P18T (p.Pro18Thr), cosmic curated COSV10724, TOPMed rs1178810605, gnomAD rs1178810605, Uncertain significance
- P18P (p.Pro18Pro), rs547238917, gnomAD 3-179198879-A-C, CADD 12.00
- R19* (p.Arg19Ter), Ensembl rs2108385158
- R19G (p.Arg19Gly), Ensembl rs2108385158, REVEL 0.33, CADD 19.90
- R19I (p.Arg19Ile), NCI-TCGA Cosmic COSV5593, Ensembl rs2108385161, Variant assessed as somatic; moderate impact.
- R19K (p.Arg19Lys), cosmic curated COSV55934, Ensembl rs2108385161, REVEL 0.16, CADD 21.40
- R19S (p.Arg19Ser), Ensembl rs2108385169
- R19T (p.Arg19Thr), Ensembl rs2108385161
- I20F (p.Ile20Phe), Ensembl rs2108385176
- I20N (p.Ile20Asn), Ensembl rs2108385180
- I20T (p.Ile20Thr), Ensembl rs2108385180
- L21I (p.Leu21Ile), rs781473521, ClinGen CA355270715, ClinVar RCV003590947, ExAC rs781473521, AlphaMissense 0.06, MetaLR 0.18, Uncertain significance, Cowden syndrome
- L21P (p.Leu21Pro), Ensembl rs2108385194
- L21V (p.Leu21Val), ExAC rs781473521, TOPMed rs781473521, Likely benign
- V22A (p.Val22Ala), Ensembl rs2108385207
- V22E (p.Val22Glu), Ensembl rs2108385207
- V22G (p.Val22Gly), Ensembl rs2108385207
- V22I (p.Val22Ile), ExAC rs748316866, TOPMed rs748316866, gnomAD rs748316866, REVEL 0.24, CADD 23.70, Uncertain significance, Inborn genetic diseases
- V22L (p.Val22Leu), ExAC rs748316866, TOPMed rs748316866, gnomAD rs748316866, Uncertain significance
- V22del (p.Val22del), gnomAD 3-179198886-CTAG-, CADD 20.10
- V22V (p.Val22Val), rs1051398, gnomAD 3-179198891-A-G, CADD 8.91
- E23D (p.Glu23Asp), rs2473886420, ClinGen CA355270788, ClinVar RCV004524023, Uncertain significance, Inborn genetic diseases
- E23K (p.Glu23Lys), Ensembl rs2108385216
- E23Q (p.Glu23Gln), Ensembl rs2108385216
- E23V (p.Glu23Val), Ensembl rs2108385221
- E23E (p.Glu23Glu), gnomAD 3-179198894-A-G, CADD 12.00
- C24* (p.Cys24Ter), Ensembl rs2108385234
- C24G (p.Cys24Gly), Ensembl rs1724334485
- C24S (p.Cys24Ser), cosmic curated COSV55965, Ensembl rs1724334485
- C24W (p.Cys24Trp), Ensembl rs2108385234
- C24Y (p.Cys24Tyr), Ensembl rs2108385228
- L25F (p.Leu25Phe), Ensembl rs2108385243
- L25I (p.Leu25Ile), Ensembl rs2108385240
- L26I (p.Leu26Ile), Ensembl rs2108385250, Likely benign
- L26P (p.Leu26Pro), Ensembl rs2108385255
- L26Q (p.Leu26Gln), Ensembl rs2108385255
- L26V (p.Leu26Val), Ensembl rs2108385250, Likely benign
- L26L (p.Leu26Leu), rs2108385250, gnomAD 3-179198901-C-T, CADD 9.92
- P27L (p.Pro27Leu), cosmic curated COSV99029, Ensembl rs2108385266
- P27Q (p.Pro27Gln), Ensembl rs2108385266
- P27R (p.Pro27Arg), Ensembl rs2108385266
- P27S (p.Pro27Ser), Ensembl rs2108385264
- P27P (p.Pro27Pro), rs1724334562, gnomAD 3-179198906-A-G, CADD 13.10
- N28S (p.Asn28Ser), gnomAD rs1724334653, REVEL 0.43, CADD 23.40
- N28Y (p.Asn28Tyr), Ensembl rs2108385275
- N28N (p.Asn28Asn), gnomAD 3-179198909-T-C, CADD 11.10
- G29* (p.Gly29Ter), Ensembl rs1724334769
- G29A (p.Gly29Ala), Ensembl rs2108385285
- G29E (p.Gly29Glu), Ensembl rs2108385285
- G29R (p.Gly29Arg), Ensembl rs1724334769
- G29V (p.Gly29Val), Ensembl rs2108385285
- M30I (p.Met30Ile), ESP rs372968114, ExAC rs372968114, TOPMed rs372968114, gnomAD rs372968114, REVEL 0.35, CADD 19.50
- M30K (p.Met30Lys), Ensembl rs2108385295
- M30L (p.Met30Leu), gnomAD rs1289478729, REVEL 0.36, CADD 21.50, Uncertain significance, Inborn genetic diseases
- M30R (p.Met30Arg), Ensembl rs2108385295
- M30V (p.Met30Val), gnomAD rs1289478729, REVEL 0.41, CADD 19.10, Uncertain significance, not provided
- I31K (p.Ile31Lys), Ensembl rs1724335162, Uncertain significance
- I31L (p.Ile31Leu), rs1724335079, Ensembl rs1724335079, ClinGen CA355270972, ClinVar RCV001066888, REVEL 0.25, CADD 21.30, Uncertain significance, Inborn genetic diseases; Cowden syndrome
- I31M (p.Ile31Met), rs2108385317, ClinGen CA355270988, cosmic curated COSV55898, ClinVar RCV001837031, AlphaMissense 0.07, MetaLR 0.16, Uncertain significance, Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR p
- I31R (p.Ile31Arg), Ensembl rs1724335162, Uncertain significance
- I31T (p.Ile31Thr), cosmic curated COSV10724, Ensembl rs1724335162, Uncertain significance, Inborn genetic diseases
- I31V (p.Ile31Val), gnomAD 3-179198916-A-G, REVEL 0.14, CADD 19.60
- V32E (p.Val32Glu), Ensembl rs2108385331
- V32G (p.Val32Gly), Ensembl rs2108385331
- V32L (p.Val32Leu), Ensembl rs2108385324
- V32M (p.Val32Met), Ensembl rs2108385324
- V32V (p.Val32Val), rs1724335252, gnomAD 3-179198921-G-C, CADD 9.62
- T33I (p.Thr33Ile), rs2108385343, ClinGen CA355271068, ClinVar RCV002387456, Ensembl rs2108385343, AlphaMissense 0.07, MetaLR 0.14, Uncertain significance, Inborn genetic diseases
- T33N (p.Thr33Asn), Ensembl rs2108385343, Uncertain significance
- T33S (p.Thr33Ser), Ensembl rs2108385343, Uncertain significance
- L34* (p.Leu34Ter), Ensembl rs2108385359, Uncertain significance
- L34F (p.Leu34Phe), Ensembl rs2108385361
- L34S (p.Leu34Ser), Ensembl rs2108385359, Uncertain significance, not provided
- E35D (p.Glu35Asp), gnomAD rs1175550125, Likely benign
- E35K (p.Glu35Lys), Ensembl rs2108385365, Uncertain significance
- E35Q (p.Glu35Gln), rs2108385365, ClinGen CA355271107, ClinVar RCV001889112, ClinVar RCV004041377, REVEL 0.38, CADD 23.90, Uncertain significance, Cowden syndrome; Inborn genetic diseases
- E35V (p.Glu35Val), Ensembl rs2108385371
- E35E (p.Glu35Glu), rs1175550125, gnomAD 3-179198930-A-G, CADD 10.60
- C36* (p.Cys36Ter), Ensembl rs2108385398
- C36G (p.Cys36Gly), ExAC rs777956032, gnomAD rs777956032
- C36R (p.Cys36Arg), ExAC rs777956032, gnomAD rs777956032, REVEL 0.85, CADD 27.60
- C36S (p.Cys36Ser), Ensembl rs2108385390
- C36W (p.Cys36Trp), Ensembl rs2108385398
- C36Y (p.Cys36Tyr), NCI-TCGA Cosmic COSV9983, cosmic curated COSV99837, Ensembl rs2108385390, Variant assessed as somatic; moderate impact.
- C36F (p.Cys36Phe), gnomAD 3-179198932-G-T, REVEL 0.69, CADD 27.30
- L37F (p.Leu37Phe), cosmic curated COSV10506, Ensembl rs2108385405
- L37H (p.Leu37His), Ensembl rs2108385413
- L37I (p.Leu37Ile), Ensembl rs2108385405
- L37P (p.Leu37Pro), Ensembl rs2108385413
- L37V (p.Leu37Val), Ensembl rs2108385405
- L37L (p.Leu37Leu), rs2108385417, gnomAD 3-179198936-C-A, CADD 9.70
- R38C (p.Arg38Cys), rs749415085, ClinGen CA2710497, NCI-TCGA Cosmic COSV5587, cosmic curated COSV55874, REVEL 0.74, CADD 28.70, Uncertain significance, not provided; Cowden syndrome
- R38G (p.Arg38Gly), cosmic curated COSV55892, ExAC rs749415085, gnomAD rs749415085, Uncertain significance, in CRC
Public PIK3CA analysis runs
- PIK3CA analysis run — PIK3CA (4,169 variants) — completed 2026-09-20
- PIK3CA analysis run — PIK3CA (4,225 variants) — completed 2026-08-09