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PIK3CA

phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha

The PIK3CA gene provides instructions for a crucial enzyme involved in fundamental cellular processes such as growth, division, and survival. The PIK3CA gene encodes the p110 alpha subunit of phosphatidylinositol 3-kinase (PI3K), an enzyme central to cell signalling pathways.

Chromosome 3q26.32 AD (somatic/mosaic) HGNC:8975 Tier B
PIK3CA 3q26.32 p arm q arm 3

PIK3CA is located on the long (q) arm of chromosome 3, at band 3q26.32. Arm ratio per GRCh38 - banding schematic.

Explore chromosome 3 in the library →

Overview

The PIK3CA gene, fully named phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, plays a critical role in cellular function. It provides the blueprint for a catalytic subunit of the enzyme phosphatidylinositol 3-kinase (PI3K). This enzyme is a key player in multiple cellular processes, including cell growth, proliferation, movement, and survival.

Dysregulation of PIK3CA activity, often due to somatic or mosaic variants, can lead to various conditions. These include overgrowth syndromes and have been implicated in the development and progression of certain cancers. Understanding PIK3CA's function and its associated variants is important for diagnosing and potentially managing these conditions.

What the gene does

The PIK3CA gene codes for the p110 alpha protein, which serves as the catalytic subunit of the PI3K enzyme. As a kinase, PI3K's primary role is to attach a phosphate group to specific signalling molecules within the cell. This phosphorylation initiates a cascade of downstream reactions, effectively transmitting chemical signals that regulate diverse cellular activities.

Key functions influenced by PI3K signalling include cell growth and division (proliferation), cellular movement (migration), the synthesis of new proteins, intracellular transport, and cell survival. Research indicates that PI3K signalling may also be involved in regulating several hormones and contributing to the maturation of fat cells (adipocytes).

The p110 alpha subunit is responsible for PI3K's enzymatic action, while other subunits, encoded by different genes, help regulate its activity. Precise control of PI3K activity is essential for maintaining normal cellular balance, and disruptions can lead to significant physiological consequences.

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Chromosome location

The PIK3CA gene is located on chromosome 3, specifically at band 3q26.32. This position refers to a precise segment on the long arm (q) of chromosome 3. The gene spans a region on the human genome, providing the genetic blueprint for the p110 alpha protein. Its location on chromosome 3 makes it part of the intricate genomic landscape, where its expression and regulation are coordinated with other nearby genes.

Protein structure

The p110 alpha protein, encoded by the PIK3CA gene, consists of 1068 amino acids and exhibits a complex domain architecture essential for its catalytic activity. It contains several distinct functional domains. The PI3K-ABD domain is located from amino acids 16-105, followed by the PI3K-RBD domain spanning amino acids 187-289. A C2 PI3K-type domain is found between amino acids 330-487.

The PIK helical domain is situated from amino acids 517-694. The critical PI3K/PI4K catalytic domain, responsible for the enzyme's phosphorylation activity, spans amino acids 765-1051. Within this catalytic domain, specific regions are further defined: the G-loop from amino acids 771-777, the Catalytic loop from amino acids 912-920, and the Activation loop from amino acids 931-957. Each domain and region contributes to the overall function and regulation of the PI3K enzyme.

Domain map · 1,068 amino acids
PI3K-ABD (16–105)PI3K-RBD (187–289)C2 PI3K-type (330–487)PIK helical (517–694)PI3K/PI4K catalytic (765–1051)G-loop (771–777)Catalytic loop (912–920)Activation loop (931–957)C2 PI3K330–487PIK helical517–694PI3K/PI4K catalytic765–10511~5341,068
Domain - independent functional unit
Region - functional region
🧬 Explore 3D structure on AlphaFold
UniProt:P42336Length:1,068 aaStructure:AlphaFold

Key variants

Variants in the PIK3CA gene can alter the function of the p110 alpha protein, leading to various health implications. These genetic changes are often somatic or mosaic, meaning they arise after conception and are present in only a subset of the body's cells, rather than being inherited from parents in every cell. The spectrum of PIK3CA variants includes point mutations, insertions, and deletions that can affect different domains of the protein. The impact of a specific variant depends on its location and the nature of the change, often resulting in increased PI3K enzyme activity. These activating variants are frequently implicated in cellular overgrowth and can contribute to tumour formation.

1,526
Total variants catalogued in ClinVar
View all on ClinVar →
112 Pathogenic / Likely pathogenic 643 Uncertain significance 746 Benign / Likely benign 25 Conflicting or other

Sample of pathogenic variants

10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.

Variant (HGVS) Protein change Classification Evidence Associated condition
c.1624G>A
single nucleotide variant
 p.Glu542Lys Pathogenic ★★★☆ Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes
c.2176G>A
single nucleotide variant
 p.Glu726Lys Pathogenic ★★★☆ Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes
c.2740G>A
single nucleotide variant
 p.Gly914Arg Pathogenic ★★★☆ Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes
c.3140A>G
single nucleotide variant
 p.His1047Arg Pathogenic ★★★☆ Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes
c.1030G>A
single nucleotide variant
 p.Val344Met Pathogenic ★★☆☆ not provided
c.1034A>G
single nucleotide variant
 p.Asn345Ser Pathogenic/Likely pathogenic ★★☆☆ PIK3CA related overgrowth syndrome
c.1035T>A
single nucleotide variant
 p.Asn345Lys Pathogenic ★★☆☆ Abnormal cardiovascular system morphology
c.1048G>A
single nucleotide variant
 p.Asp350Asn Pathogenic/Likely pathogenic ★★☆☆ not provided
c.1049A>G
single nucleotide variant
 p.Asp350Gly Pathogenic ★★☆☆ Inborn genetic diseases
c.1090G>A
single nucleotide variant
 p.Gly364Arg Pathogenic/Likely pathogenic ★★☆☆ not provided

Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.

Associated conditions

Variants in the PIK3CA gene are associated with a range of conditions, primarily characterised by overgrowth or abnormal tissue development. These conditions often arise from somatic or mosaic variants, leading to localised or segmental overgrowth. Recognised conditions include CLOVES syndrome, Fibroadipose hyperplasia, Hemimegalencephaly, Klippel-Trenaunay syndrome, Megalencephaly-capillary malformation syndrome, and Somatic PIK3CA overgrowth (macrodactyly). Collectively, these are often referred to as PIK3CA-related overgrowth spectrum (PROS). Additionally, PIK3CA variants have been linked to Cowden-like syndrome (KLLN/PIK3CA/AKT1) and have been identified in some cases of bladder cancer.

Inheritance pattern

Conditions caused by pathogenic PIK3CA variants typically follow ad (somatic/mosaic) inheritance.

♀ Affected parent 1 altered copy ♂ Unaffected parent 2 typical copies Affected Unaffected Unaffected Affected Affected Carrier Unaffected Circles = females · Squares = males

Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.

UK clinical status

In the UK, the PIK3CA gene is recognised on several NHS Genomic Medicine Service (GMS) approved panels, indicating its clinical significance for diagnosis and management. It is included in the 'green' tier for conditions such as Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders, DDG2P, Foetal anomalies (R21), Hydrocephalus (R86), Intellectual disability, and Limb disorders. Furthermore, PIK3CA is part of panels for Malformations of cortical development, Neurological segmental overgrowth, and Pigmentary skin disorders (R236). Deep sequencing panels also cover PIK3CA for Mosaic skin disorders (R327), Segmental overgrowth disorders (R110), and Vascular skin disorders (R326), reflecting the importance of detecting low-level mosaic variants.

Green-listed
High evidence · clinically actionable in NHS testing
Included in NHS GMS signed-off panels
Fetal anomalies · R21 NHS GMS → Hydrocephalus · R86 NHS GMS → Mosaic skin disorders - Deep sequencing · R327 NHS GMS → Pigmentary skin disorders · R236 NHS GMS → Segmental overgrowth disorders - Deep sequencing · R110 NHS GMS → Vascular skin disorders · R326 NHS GMS → DDG2P NHS GMS → Intellectual disability NHS GMS →
NHS Genomic Medicine Service Jeen carrier screening

Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory

Diet & lifestyle considerations

Given the role of PIK3CA in cellular growth and signalling, general healthy lifestyle choices are often recommended for overall well-being. Maintaining a balanced diet rich in fruits, vegetables, and whole grains, combined with regular physical activity, supports cellular health. Avoiding excessive consumption of processed foods and saturated fats may also contribute to a healthy cellular environment. Research suggests that lifestyle factors can influence general cellular processes; however, there is no conclusive evidence that specific lifestyle interventions can prevent conditions associated with PIK3CA variants or alter their progression.

Supplement considerations

There is currently no scientific evidence to suggest that specific dietary supplements can prevent, treat, or cure conditions associated with PIK3CA gene variants. While some supplements are marketed for general cellular health or anti-inflammatory properties, their direct impact on PIK3CA-related conditions has not been established. Individuals considering any supplements should consult with a healthcare professional to discuss potential benefits, risks, and interactions with other medications or health conditions.

Frequently asked questions

What is the main function of the PIK3CA gene?

The PIK3CA gene provides instructions for the p110 alpha subunit of the PI3K enzyme, which is crucial for adding phosphate groups to signalling molecules, thereby regulating cell growth, division, migration, and survival.

Are conditions related to PIK3CA inherited?

Conditions associated with PIK3CA are typically caused by somatic or mosaic variants, meaning they are not usually inherited from parents but arise spontaneously in some cells after conception. This results in the condition affecting only certain parts of the body.

What types of conditions are linked to PIK3CA variants?

PIK3CA variants are linked to various overgrowth syndromes, collectively known as PIK3CA-related overgrowth spectrum (PROS), including CLOVES syndrome, Klippel-Trenaunay syndrome, and Megalencephaly-capillary malformation syndrome. They are also implicated in some cancers.

Is PIK3CA relevant to cancer development?

Yes, somatic variants in the PIK3CA gene have been identified in certain cancers, including bladder cancer. These variants often lead to increased PI3K enzyme activity, which can promote uncontrolled cell growth and tumour formation.

How does PIK3CA activity affect cells?

PIK3CA's role in the PI3K enzyme pathway influences numerous cell activities such as cell proliferation (growth and division), cell migration, protein production, and the overall survival of cells, making it fundamental to cellular function.

References

  1. Robertson AG, Kim J, Al-Ahmadie H. Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer. Cell. 2018. PMID: 30096301
  2. Vahidnezhad H, Youssefian L, Uitto J. Klippel-Trenaunay syndrome belongs to the PIK3CA-related overgrowth spectrum (PROS). Experimental dermatology. 2016. PMID: 26268729
  3. Luks VL, Kamitaki N, Vivero MP. Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA. The Journal of pediatrics. 2015. PMID: 25681199
  4. Kurek KC, Luks VL, Ayturk UM. Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. American journal of human genetics. 2012. PMID: 22658544
  5. Lindhurst MJ, Parker VE, Payne F. Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. Nature genetics. 2012. PMID: 22729222
  6. Lee JH, Huynh M, Silhavy JL. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nature genetics. 2012. PMID: 22729223
  7. Rivière JB, Mirzaa GM, O'Roak BJ. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nature genetics. 2012. PMID: 22729224
  8. Zhao L, Vogt PK. Hot-spot mutations in p110alpha of phosphatidylinositol 3-kinase (pI3K): differential interactions with the regulatory subunit p85 and with RAS. Cell cycle (Georgetown, Tex.). 2010. PMID: 20009532
  9. Graupera M, Guillermet-Guibert J, Foukas LC. Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration. Nature. 2008. PMID: 18449193
  10. Zhao L, Vogt PK. Class I PI3K in oncogenic cellular transformation. Oncogene. 2008. PMID: 18794883
  11. Hafner C, López-Knowles E, Luis NM. Oncogenic PIK3CA mutations occur in epidermal nevi and seborrheic keratoses with a characteristic mutation pattern. Proceedings of the National Academy of Sciences of the United States of America. 2007. PMID: 17673550
  12. Adam MP, Bick S, Mirzaa GM. PIK3CA-Related Overgrowth Spectrum. 1993. PMID: 23946963
Educational content. This page is not medical or genetic advice, is not individually reviewed by a clinician for each reader, and should not replace a consultation with a qualified healthcare professional or genetic counsellor. If you are considering genetic testing or acting on a test result, book a consultation.
Data sources Last updated 18 October 2026. Content compiled from HGNC · MedlinePlus Genetics · ClinGen · Genomics England PanelApp · NHS National Genomic Test Directory · ClinVar · UniProt · AlphaFold .