Book a test
On this page
⚠ Educational content only Not medical or genetic advice. Speak with a healthcare provider or genetic counsellor before acting on anything here.

PIK3CA

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

The PIK3CA gene provides instructions for a subunit of phosphatidylinositol 3-kinase (PI3K), an enzyme crucial for regulating cell growth, division, and survival. PIK3CA encodes the p110 alpha protein, a catalytic component of the PI3K enzyme.

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 contains the genetic blueprint for a crucial component of the phosphatidylinositol 3-kinase (PI3K) enzyme. This enzyme plays a central role in a variety of cellular functions, including cell growth, proliferation, movement, and survival. Proper PIK3CA function is essential for normal development and tissue maintenance.

Pathogenic changes or variants within the PIK3CA gene can disrupt these fundamental cellular processes. This disruption can lead to uncontrolled cell growth and abnormal tissue development, contributing to the aetiology of various overgrowth syndromes and certain types of cancer. Understanding the mechanisms by which PIK3CA influences cell biology is key to comprehending these associated health conditions.

What the gene does

The PIK3CA gene directs the production of the p110 alpha (p110α) protein, which serves as the catalytic subunit of the phosphatidylinositol 3-kinase (PI3K) enzyme. While other subunits regulate PI3K activity, p110α is responsible for the enzyme's primary action: phosphorylation. Phosphorylation involves adding a phosphate group to specific signalling molecules within the cell. This enzymatic activity triggers a cascade of subsequent reactions, effectively transmitting chemical signals throughout the cell.

PI3K signalling is fundamental for numerous cellular activities. It influences cell growth and division (proliferation), the movement of cells (migration), the synthesis of new proteins, and the transport of materials within the cell. Additionally, it is critical for cell survival mechanisms. Research indicates that PI3K signalling may also be involved in regulating several hormones and plays a part in the maturation of fat cells (adipocytes). Consequently, the proper functioning of the PIK3CA-encoded protein is indispensable for maintaining cellular homeostasis and coordinating vital biological processes.

Video: Genetics 101

Chromosome location

The PIK3CA gene is situated on the long arm of chromosome 3, specifically at position 3q26.32. This genomic location indicates its precise address within the human genome. The gene spans a significant region of DNA, and its transcriptional activity leads to the production of messenger RNA that is then translated into the p110 alpha protein.

Protein structure

The p110 alpha protein, encoded by the PIK3CA gene, is composed of 1068 amino acids and features several distinct functional domains critical for its enzymatic activity and interactions. Starting from the N-terminus, it includes the PI3K-ABD domain, located between amino acids 16 and 105. Following this is the PI3K-RBD domain, spanning amino acids 187 to 289. The C2 PI3K-type domain is found between amino acids 330 and 487.

Further along the protein sequence, the PIK helical domain is present from amino acids 517 to 694. The core catalytic activity is housed within the PI3K/PI4K catalytic domain, which extends from amino acids 765 to 1051. Within this catalytic domain, specific regions are further defined: the G-loop from amino acids 771 to 777, the Catalytic loop from 912 to 920, and the Activation loop from 931 to 957. These domains and regions work in concert to facilitate the protein's role in cellular signalling.

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 within the PIK3CA gene can manifest in several ways, leading to altered protein function. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions, impacting the production or activity of the p110 alpha protein. Many pathogenic PIK3CA variants are somatic or mosaic, meaning they arise after conception and are present only in specific cells or tissues, rather than being inherited from parents in every cell of the body. The specific location and nature of a PIK3CA variant often determine the resulting clinical phenotype, influencing the severity and type of associated condition.

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 spectrum of conditions, primarily involving overgrowth and vascular malformations, often exhibiting a somatic or mosaic inheritance pattern. These include conditions such as CLOVES syndrome, Fibroadipose hyperplasia, Hemimegalencephaly, Klippel-Trenaunay syndrome, Megalencephaly-capillary malformation syndrome, and Somatic PIK3CA overgrowth (macrodactyly), which are collectively referred to as PIK3CA-related overgrowth spectrum (PROS). Additionally, PIK3CA variants are implicated in Cowden-like syndrome (KLLN/PIK3CA/AKT1), which can follow an autosomal dominant inheritance pattern. Variants are also linked to bladder cancer and certain types of epidermal naevi.

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 testing panels, underscoring its clinical significance. It is part of panels for Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders, and is included in the Developmental Disorders Genomics Panel (DDG2P). PIK3CA is also assessed in the context of Foetal anomalies, Hydrocephalus, Intellectual disability, and Limb disorders. Furthermore, deep sequencing for PIK3CA is relevant for Mosaic skin disorders (R327), Neurological segmental overgrowth, Pigmentary skin disorders (R236), Segmental overgrowth disorders (R110), and Vascular skin disorders (R326), highlighting its broad involvement in developmental and overgrowth conditions.

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

Research into the direct impact of specific lifestyle factors on individuals with PIK3CA variants is ongoing and often complex due to the varied nature of associated conditions. Generally, maintaining a balanced diet, engaging in regular physical activity suitable for an individual's specific health status, and avoiding smoking and excessive alcohol consumption are recognised as beneficial for overall health. These general healthy lifestyle choices may support well-being, but there is no conclusive evidence that they can prevent the development or alter the progression of conditions caused by PIK3CA variants. Individuals should discuss any lifestyle changes with a healthcare professional.

Supplement considerations

There is currently no definitive scientific evidence to suggest that specific dietary supplements can prevent, treat, or mitigate the effects of conditions associated with PIK3CA gene variants. While some supplements are marketed for general health benefits, their efficacy in directly addressing PIK3CA-related conditions has not been established. Individuals considering taking any supplements should consult with their healthcare provider to ensure safety and appropriateness, particularly given potential interactions with existing health conditions or medications.

Frequently asked questions

What is the primary function of the PIK3CA gene?

The PIK3CA gene provides instructions for making the p110 alpha protein, a catalytic subunit of the phosphatidylinositol 3-kinase (PI3K) enzyme. This enzyme adds phosphate groups to other molecules, playing a critical role in cell growth, division, migration, and survival.

What types of conditions are associated with PIK3CA variants?

Variants in the PIK3CA gene are primarily associated with a group of overgrowth syndromes, often with somatic or mosaic inheritance. These include conditions like CLOVES syndrome, Klippel-Trenaunay syndrome, and Megalencephaly-capillary malformation syndrome, as well as certain cancers.

How does PIK3CA relate to cell growth?

The PIK3CA-encoded protein is a key component of the PI3K signalling pathway, which is a major regulator of cell growth and proliferation. When PIK3CA function is altered, this pathway can become dysregulated, leading to uncontrolled or abnormal cell growth.

Are PIK3CA variants typically inherited?

Many pathogenic PIK3CA variants are somatic or mosaic, meaning they arise spontaneously after conception in specific cells and are not inherited from parents. However, some conditions associated with PIK3CA, such as Cowden-like syndrome, can have an autosomal dominant inheritance pattern.

Can lifestyle changes or supplements help with PIK3CA-related conditions?

While a healthy lifestyle generally supports well-being, there is no conclusive evidence that specific lifestyle changes or dietary supplements can prevent or alter the progression of conditions caused by PIK3CA variants. Any decisions regarding lifestyle or supplements should be discussed with a healthcare professional.

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 27 September 2026. Content compiled from HGNC · MedlinePlus Genetics · ClinGen · Genomics England PanelApp · NHS National Genomic Test Directory · ClinVar · UniProt · AlphaFold .