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…

Primary Disease Associations & Inheritance

?Roifman-Chitayat syndrome, digenicMIM #613328

Digenic recessive

Immunodeficiency 14A, autosomal dominantMIM #615513

Immunodeficiency 14B, autosomal recessiveMIM #619281

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

121

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.20

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

📖

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

Background carrier burden — how many people carry a rare variant somewhere in PIK3CD?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 67

905 rare PASS variants

Rare truncating (LoF)

1 in 4,500

69 rare PASS variants

Rare synonymous (reference)

1 in 51

664 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PIK3CD. 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 68	1 in 7,100
South Asian	~43k	1 in 66	1 in 1,200
Remaining (unassigned)	~30k	1 in 71	≈ 1 in 7,400
European (Finnish)	~27k	1 in 140	≈ 1 in 7,300
Admixed American	~22k	1 in 59	≈ 1 in 4,500
African / African American	~21k	1 in 54	1 in 3,800
East Asian	~20k	1 in 70	≈ 1 in 4,700
Ashkenazi Jewish	~13k	1 in 480	none seen
Middle Eastern	~2,884	1 in 72	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 21 of 22 coding exons well covered in gnomAD exomes; exon 12 marginal. Genomes: 21 of 22 (exon 12 below).? see exons ↓