PI4KA

Chr 22AR

phosphatidylinositol 4-kinase alpha

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

NCBI Gene: 5297 ENSG00000241973 UniProt: P42356 OMIM: 600286

This protein catalyzes the phosphorylation of phosphatidylinositol to produce phosphatidylinositol 4-phosphate, the first committed step in generating the second messenger inositol-1,4,5-trisphosphate. Autosomal recessive mutations cause a spectrum of disorders including gastrointestinal defects with immunodeficiency, perisylvian polymicrogyria with cerebellar hypoplasia and arthrogryposis, and spastic paraplegia. Loss of function disrupts phosphoinositide signaling pathways critical for normal development and cellular function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.463 OMIM phenotypes

Clinical Summary— PI4KA

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

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?

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?

LoF OE?0.36 (0.28–0.46)

0≤0.351.4

Missense OE?0.72 (0.68–0.76)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 43 / 120.3Missense obs/exp: 883 / 1231.3Syn Z: -0.24

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePI4KA-related polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposisLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6453th %ile

GOF

0.6150th %ile

LOF

0.3842th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.