PI4KA

Chr 22AR

phosphatidylinositol 4-kinase alpha

Also known as: GIDID2, PI4K-ALPHA, PIK4CA, PMGYCHA, SPG84, pi4K230

NCBI Gene: 5297ENSG00000241973UniProt: P42356

This gene encodes a phosphatidylinositol (PI) 4-kinase which catalyzes the first committed step in the biosynthesis of phosphatidylinositol 4,5-bisphosphate. The mammalian PI 4-kinases have been classified into two types, II and III, based on their molecular mass, and modulation by detergent and adenosine. The protein encoded by this gene is a type III enzyme that is not inhibited by adenosine. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Apr 2018]

Primary Disease Associations & Inheritance

Gastrointestinal defects and immunodeficiency syndrome 2MIM #619708
AR
Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposisMIM #616531
AR
Spastic paraplegia 84, autosomal recessiveMIM #619621
AR
UniProtNeurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities
540
ClinVar variants
167
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— PI4KA
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
167 Pathogenic / Likely Pathogenic· 175 VUS of 540 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Missense constrained — critical functional residues
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.
0.46LOEUF
pLI 0.000
Z-score 6.53
OE 0.36 (0.28–0.46)
Moderately constrained

More LoF-intolerant than ~75% 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.
3.53Z-score
OE missense 0.72 (0.68–0.76)
883 obs / 1231.3 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.36 (0.28–0.46)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.72 (0.68–0.76)
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.1.01
0≤1.21.6
LoF obs/exp: 43 / 120.3Missense obs/exp: 883 / 1231.3Syn Z: -0.24

ClinVar Variant Classifications

540 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic142
Likely Pathogenic25
VUS175
Likely Benign82
Benign113
Conflicting3
142
Pathogenic
25
Likely Pathogenic
175
VUS
82
Likely Benign
113
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
4
5
133
0
142
Likely Pathogenic
6
8
11
0
25
VUS
4
127
44
0
175
Likely Benign
0
8
13
61
82
Benign
0
1
99
13
113
Conflicting
—3
Total1414930074540

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

View in ClinVar →

Protein Context — Lollipop Plot

PI4KA · protein map & ClinVar variants

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

Gene2Phenotype Curations

PI4KA-related polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Gastrointestinal defects and immunodeficiency syndrome 2

MIM #619708

Molecular basis of disorder known

Autosomal recessive

Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis

MIM #616531

Molecular basis of disorder known

Autosomal recessive

Spastic paraplegia 84, autosomal recessive

MIM #619621

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — PI4KA
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Biallelic PI4KA Mutations Disrupt B-Cell Metabolism and Cause B-Cell Lymphopenia and Hypogammaglobulinemia.
Saettini F et al.·J Clin Immunol
2024
Genetic Heterogeneity Underlying Phenotypes with Early-Onset Cerebellar Atrophy.
Martínez-Rubio D et al.·Int J Mol Sci
2023
A synonymous mutation in PI4KA impacts the transcription and translation process of gene expression.
Zhang K et al.·Front Immunol
2022
Malignancy in Adults with Inborn Errors of Immunity: A Retrospective Single-Center Study.
Gumusburun R et al.·J Clin Immunol
2025
Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis.
Pagnamenta AT et al.·Hum Mol Genet
2015
Mapping the Proteomic Landscape of Pancreatic Cancer: Prognostic Insights and Subtype Stratification.
Aref AT et al.·Cancer Res Commun
2025
Identifying novel heterozygous PI4KA variants in fetal abnormalities.
Cheng C et al.·BMC Med Genomics
2025Case report
Identification of genetic modifiers enhancing B7-H3-targeting CAR T cell therapy against glioblastoma through large-scale CRISPRi screening.
Li X et al.·J Exp Clin Cancer Res
2024
Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity.
Adhikari H et al.·Nat Commun
2021
Extrachromosomal circular DNAs in the differentiation of human bone marrow mesenchymal stem cells.
Gu Y et al.·Stem Cell Res Ther
2025
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools