PIK3R1

Chr 5

phosphoinositide-3-kinase regulatory subunit 1

Also known as: AGM7, GRB1, IMD36, p85, p85-ALPHA, p85alpha

NCBI Gene: 5295ENSG00000145675UniProt: P27986

Phosphatidylinositol 3-kinase phosphorylates the inositol ring of phosphatidylinositol at the 3-prime position. The enzyme comprises a 110 kD catalytic subunit and a regulatory subunit of either 85, 55, or 50 kD. This gene encodes the 85 kD regulatory subunit. Phosphatidylinositol 3-kinase plays an important role in the metabolic actions of insulin, and a mutation in this gene has been associated with insulin resistance. Alternative splicing of this gene results in four transcript variants encoding different isoforms. [provided by RefSeq, Jun 2011]

Primary Disease Associations & Inheritance

UniProtAgammaglobulinemia 7, autosomal recessive
UniProtSHORT syndrome
UniProtImmunodeficiency 36 with lymphoproliferation
767
ClinVar variants
42
Pathogenic / LP
1.00
pLI score· haploinsufficient
4
Active trials
Clinical Summary— PIK3R1
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
42 Pathogenic / Likely Pathogenic· 245 VUS of 767 total submissions
💊
Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.23LOEUF
pLI 1.000
Z-score 5.61
OE 0.11 (0.06–0.23)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.
2.72Z-score
OE missense 0.62 (0.55–0.69)
245 obs / 397.7 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.11 (0.06–0.23)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.62 (0.55–0.69)
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.0.84
0≤1.21.6
LoF obs/exp: 5 / 46.1Missense obs/exp: 245 / 397.7Syn Z: 1.56

ClinVar Variant Classifications

767 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic24
Likely Pathogenic18
VUS245
Likely Benign216
Benign33
Conflicting4
24
Pathogenic
18
Likely Pathogenic
245
VUS
216
Likely Benign
33
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
9
1
14
0
24
Likely Pathogenic
8
2
8
0
18
VUS
3
206
31
5
245
Likely Benign
0
4
93
119
216
Benign
0
0
32
1
33
Conflicting
—4
Total20213178125540

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

View in ClinVar →

Protein Context — Lollipop Plot

PIK3R1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

PIK3R1-related agammaglobulinemia

limited
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

PIK3R1-related SHORT syndrome

definitive
ADUndeterminedAltered Gene Product Structure
Dev. DisordersEye
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Comprehensive genomic characterization defines human glioblastoma genes and core pathways.
Cancer Genome Atlas Research Network·Nature
2008
Autophagy in the physiological endometrium and cancer.
Devis-Jauregui L et al.·Autophagy
2021Review
Clinical, Immunological, and Genetic Features in Patients with Activated PI3Kδ Syndrome (APDS): a Systematic Review.
Jamee M et al.·Clin Rev Allergy Immunol
2020Meta-analysis
An integrative analysis reveals cancer risk associated with artificial sweeteners.
Xie J et al.·J Transl Med
2025
Primary Immune Regulatory Disorders With an Autoimmune Lymphoproliferative Syndrome-Like Phenotype: Immunologic Evaluation, Early Diagnosis and Management.
López-Nevado M et al.·Front Immunol
2021
Mapping variant effects on anti-tumor hallmarks of primary human T cells with base-editing screens.
Walsh ZH et al.·Nat Biotechnol
2025
Scalable generation and functional classification of genetic variants in inborn errors of immunity to accelerate clinical diagnosis and treatment.
Walsh ZH et al.·Cell
2025Functional
A Novel Type of IDH-wildtype Glioma Characterized by Gliomatosis Cerebri-like Growth Pattern, TERT Promoter Mutation, and Distinct Epigenetic Profile.
Muench A et al.·Am J Surg Pathol
2023
Activated phosphoinositide 3-kinase δ syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity.
Maccari ME et al.·J Allergy Clin Immunol
2023
Genomic landscape of TCRαβ and TCRγδ T-large granular lymphocyte leukemia.
Cheon H et al.·Blood
2022
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Fallopian Tube Endometrioid AdenocarcinomaFallopian Tube High Grade Serous AdenocarcinomaOvarian Endometrioid Adenocarcinoma

Testing the Addition of Ipatasertib to the Usual Chemotherapy Treatment (Paclitaxel and Carboplatin) for Stage III or IV Epithelial Ovarian Cancer

ACTIVE NOT RECRUITING
NCT05276973Phase PHASE1National Cancer Institute (NCI)Started 2022-09-08
BiopsyCarboplatinIpatasertib
Lymphoma, Non-HodgkinMultiple MyelomaAdvanced Solid Tumors

Canadian Profiling and Targeted Agent Utilization Trial (CAPTUR)

RECRUITING
NCT03297606Phase PHASE2Canadian Cancer Trials GroupStarted 2018-03-23
OlaparibDasatinibNivolumab plus Ipilimumab
Malignant Solid Neoplasms

Adapting Treatment to the Tumor Molecular Alterations for Patients With Advanced Solid Tumors: MyOwnSpecificTreatment

RECRUITING
NCT02029001Phase PHASE2Centre Leon BerardStarted 2014-03
Nilotinib (400 mg BID)Everolimus (10 mg QD)Sorafenib (400 mg BID)
Lipodystrophy (Genetic or Acquired, Non HIV)

The LD Lync Study - Natural History Study of Lipodystrophy Syndromes

RECRUITING
NCT03087253University of MichiganStarted 2018-02-27

External Resources

Links to major genomics databases and tools