PIK3R3

Chr 1

phosphoinositide-3-kinase regulatory subunit 3

Also known as: p55, p55-GAMMA, p55PIK

NCBI Gene: 8503ENSG00000117461UniProt: Q92569

Phosphatidylinositol 3-kinase (PI3K) phosphorylates phosphatidylinositol and similar compounds, which then serve as second messengers in growth signaling pathways. PI3K is composed of a catalytic and a regulatory subunit. The protein encoded by this gene represents a regulatory subunit of PI3K. The encoded protein contains two SH2 domains through which it binds activated protein tyrosine kinases to regulate their activity. [provided by RefSeq, Jun 2016]

86
ClinVar variants
6
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— PIK3R3
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
6 Pathogenic / Likely Pathogenic· 66 VUS of 86 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.00LOEUF
pLI 0.000
Z-score 1.54
OE 0.68 (0.48–1.00)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.04Z-score
OE missense 0.99 (0.89–1.10)
248 obs / 250.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.68 (0.48–1.00)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.99 (0.89–1.10)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.78
0≤1.21.6
LoF obs/exp: 19 / 27.8Missense obs/exp: 248 / 250.0Syn Z: 1.59

ClinVar Variant Classifications

86 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4
Likely Pathogenic2
VUS66
Likely Benign2
Benign1
4
Pathogenic
2
Likely Pathogenic
66
VUS
2
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
4
0
4
Likely Pathogenic
0
0
2
0
2
VUS
0
49
17
0
66
Likely Benign
1
0
1
0
2
Benign
0
0
1
0
1
Total14925075

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

PIK3R3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
PIK3R3 regulates ZO-1 expression through the NF-kB pathway in inflammatory bowel disease.
Ibrahim S et al.·Int Immunopharmacol
2020
Whole genomes redefine the mutational landscape of pancreatic cancer.
Waddell N et al.·Nature
2015
PIK3R3 is upregulated in liver cancer and activates Akt signaling to control cancer growth by regulation of CDKN1C and SMC1A.
Lin W et al.·Cancer Med
2023
PIK3R3 regulates PPARα expression to stimulate fatty acid β-oxidation and decrease hepatosteatosis.
Yang X et al.·Exp Mol Med
2018
PIK3R3 promotes chemotherapeutic sensitivity of colorectal cancer through PIK3R3/NF-kB/TP pathway.
Ibrahim S et al.·Cancer Biol Ther
2018
PIK3R3 induces epithelial-to-mesenchymal transition and promotes metastasis in colorectal cancer.
Wang G et al.·Mol Cancer Ther
2014
TGF-β regulates the proliferation of lung adenocarcinoma cells by inhibiting PIK3R3 expression.
Wang G et al.·Mol Carcinog
2015
Rare-variant association analysis reveals known and new age-related hearing loss genes.
Cornejo-Sanchez DM et al.·Eur J Hum Genet
2023
Curcumin suppresses colorectal cancer development with epithelial-mesenchymal transition via modulating circular RNA HN1/miR-302a-3p/PIK3R3 axis.
Wu Z et al.·J Physiol Pharmacol
2022
Variable expression of PIK3R3 and PTEN in Ewing Sarcoma impacts oncogenic phenotypes.
Niemeyer BF et al.·PLoS One
2015
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
NONHSAT141192.2 Facilitates the Stemness and Radioresistance of Glioma Stem Cells via the Regulation of PIK3R3 and SOX2.
Wang S et al.·CNS Neurosci Ther
2025🔓 Open Access
PIK3R3 regulates differentiation and senescence of periodontal ligament stem cells and mitigates age-related alveolar bone loss by modulating FOXO1 expression.
Liu X et al.·J Adv Res
2025🔓 Open Access
FTO Facilitates Cervical Cancer Malignancy Through Inducing m6A-Demethylation of PIK3R3 mRNA.
Chen B et al.·Cancer Med
2024🔓 Open Access
ZSTK474 targeting PIK3R3 inhibits the Wilms' tumor through G0 / G1 phase arrest.
Li M et al.·PLoS One
2024🔓 Open Access
POU2F1 inhibits miR-29b1/a cluster-mediated suppression of PIK3R1 and PIK3R3 expression to regulate gastric cancer cell invasion and migration.
Xiao Y et al.·Chin Med J (Engl)
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools