PIK3CD

Chr 1Digenic recessiveADAR

phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta

Also known as: APDS, IMD14, IMD14A, IMD14B, P110DELTA, PI3K, PI3Kdelta, ROCHIS

NCBI Gene: 5293 ENSG00000171608 UniProt: O00329 OMIM: 602839

PIK3CD encodes a phosphoinositide 3-kinase that phosphorylates phosphatidylinositol derivatives to generate PIP3, mediating immune cell signaling, development, and function including B-cell receptor and T-cell receptor signaling pathways. Mutations cause immunodeficiency 14A (autosomal dominant) and immunodeficiency 14B (autosomal recessive), with digenic inheritance also reported in Roifman-Chitayat syndrome. The gene is highly constrained against loss-of-function variants (pLI 1.0, LOEUF 0.196), reflecting its essential role in immune system development and function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

Phosphoinositide 3-kinases (PI3Ks) phosphorylate inositol lipids and are involved in the immune response. The protein encoded by this gene is a class I PI3K found primarily in leukocytes. Like other class I PI3Ks (p110-alpha p110-beta, and p110-gamma), the encoded protein binds p85 adapter proteins and GTP-bound RAS. However, unlike the other class I PI3Ks, this protein phosphorylates itself, not p85 protein.[provided by RefSeq, Jul 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismDigenic recessive/AD/ARLOEUF 0.203 OMIM phenotypes

Clinical Summary— PIK3CD

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Gene-Disease Validity (ClinGen)

immunodeficiency 14b, autosomal recessive · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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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.

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ClinVar Variants

34 unique Pathogenic / Likely Pathogenic· 415 VUS of 1049 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — PIK3CD

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.20LOEUF

pLI 1.000

Z-score 6.15

OE 0.09 (0.05–0.20)

Highly constrained

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

Missense Constraint?

4.27Z-score

OE missense 0.52 (0.48–0.57)

331 obs / 633.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.09 (0.05–0.20)

0≤0.351.4

Missense OE?0.52 (0.48–0.57)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 5 / 53.6Missense obs/exp: 331 / 633.9Syn Z: -1.16

This gene — mechanism propensity

0.3693th %ile

GOF

0.4678th %ile

LOF

0.62top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF59% of P/LP variants are LoF · LOEUF 0.20

GOF1 literature citation

Literature Evidence

GOFHere we report a dominant gain of function PIK3CD mutation (E1021K) in a patient presenting with recurrent otitis media, massive splenomegaly, and persistent EBV-viraemia.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 28842185 ↗

ClinVar Variant Classifications

1049 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20

Likely Pathogenic14

VUS415

Likely Benign516

Benign57

Conflicting7

Pathogenic

Likely Pathogenic

415

VUS

516

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	17	3	0	0	20
Likely Pathogenic	3	11	0	0	14
VUS	4	360	45	6	415
Likely Benign	0	21	190	305	516
Benign	0	3	38	16	57
Conflicting	—				7
Total	24	398	273	327	1,029

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

View in ClinVar →

36 pathogenic / likely-pathogenic (of 49) ClinVar copy-number / structural variants overlap PIK3CD — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →