PI4KA

Chr 22

phosphatidylinositol 4-kinase alpha

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

NCBI Gene: 5297 ENSG00000241973 UniProt: P42356

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.

GeneReviews 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]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtNeurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities

UniProtGastrointestinal defects and immunodeficiency syndrome 2

UniProtSpastic paraplegia 84, autosomal recessive

Clinical highlights

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.46

LOEUF

LOF

Mechanism· G2P

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GeneReview available — PI4KA

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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

Background carrier burden — how many people carry a rare variant somewhere in PI4KA?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 38

2,166 rare PASS variants

Rare truncating (LoF)

1 in 610

278 rare PASS variants

Rare synonymous (reference)

1 in 33

1,113 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PI4KA. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 43	1 in 820
South Asian	~43k	1 in 36	1 in 940
Remaining (unassigned)	~30k	1 in 37	1 in 1,100
European (Finnish)	~27k	1 in 95	1 in 1,100
Admixed American	~22k	1 in 33	1 in 220
African / African American	~21k	1 in 26	1 in 450
East Asian	~20k	1 in 35	1 in 440
Ashkenazi Jewish	~13k	1 in 110	1 in 1,100
Middle Eastern	~2,884	1 in 32	1 in 460

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 47 of 55 coding exons well covered in gnomAD exomes; exons 1, 2, 3, 15, 19 and 3 more marginal. Genomes: 49 of 55 (exons 33, 34, 50, 51, 53, 54 below).? see exons ↓