Immunodeficiency 14b, autosomal recessive

Summary

Immunodeficiency 14b, autosomal recessive (MONDO:0023655) is a disease caused by PIK3CD (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: PIK3CD (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 22

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency 14b, autosomal recessive
Mondo ID	MONDO:0023655
OMIM	619281
UMLS	C5543301
MedGen	1787468
Is cancer (heuristic)	no

Also known as: IMD14B

Data availability: 22 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › immunodeficiency 14b, autosomal recessive

Related subtypes (94): B cell deficiency, T-cell immunodeficiency, complement deficiency, myalgic encephalomeyelitis/chronic fatigue syndrome, hypoproteinemia, hypercatabolic, X-linked lymphoproliferative syndrome, Wiskott-Aldrich syndrome, autosomal dominant form, immunodeficiency due to CD25 deficiency, immunodeficiency 67, primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency, immunodeficiency 35, pyogenic bacterial infections due to MyD88 deficiency, lymphoproliferative syndrome 1, FADD-related immunodeficiency, immunodeficiency 31B, Wiskott-Aldrich syndrome 2, cryptosporidiosis-chronic cholangitis-liver disease syndrome, idiopathic CD4 lymphocytopenia, immunodeficiency 23, DOCK2 deficiency, immunodeficiency 45, TFRC-related combined immunodeficiency, combined immunodeficiency, autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome, immunodeficiency due to selective anti-polysaccharide antibody deficiency, immunodeficiency 57, immunodeficiency 98 with autoinflammation, X-linked, immunodeficiency 102, immunodeficiency 74, COVID-19-related, X-linked, immunodeficiency 66, immunodeficiency 80 with or without congenital cardiomyopathy, immunodeficiency 81, immunodeficiency 82 with systemic inflammation, immunodeficiency 84, immunodeficiency 85 and autoimmunity, immunodeficiency 86, immunodeficiency 87 and autoimmunity, immunodeficiency 88, immunodeficiency 89 and autoimmunity, immunodeficiency 91 and hyperinflammation, immunodeficiency 92, immunodeficiency 93 and hypertrophic cardiomyopathy, immunodeficiency 95, immunodeficiency 96, immunodeficiency 97 with autoinflammation, immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias, immunodeficiency 101 (varicella zoster virus-specific), immunodeficiency 75, immunodeficiency 76, immunodeficiency 106, susceptibility to viral infections, immunodeficiency 78 with autoimmunity and developmental delay, immunodeficiency 77, immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection, immunodeficiency 15a, immunodeficiency 60, immunodeficiency 62, immunodeficiency 63 with lymphoproliferation and autoimmunity, immunodeficiency 64, immunodeficiency 65, susceptibility to viral infections, immunodeficiency 69, immunodeficiency 70, immunodeficiency 72 with autoinflammation, GATA2 deficiency with susceptibility to MDS/AML, Shwachman-Diamond syndrome 1, immunodeficiency 53, immunodeficiency 11b with atopic dermatitis, IKBKG-related immunodeficiency with or without ectodermal dysplasia, FNIP1-associated syndrome, FASLG-related immunodeficiency, TNFRSF9-related immunodeficiency, DNAJC21-related Shwachman Diamond syndrome, IRF4-related immune disorder, PTEN harmartoma tumor syndrome with immune disorder, primary immunodeficiency due to calcium channel deficiency, chronic mucocutaneous candidiasis and connective tissue disease due to JNK1 haploinsufficiency, immune deficiency due to impaired neutrophil phagocytosis and migration, hatipoglu immunodeficiency syndrome, immunodeficiency 112, immunodeficiency 113 with autoimmunity and autoinflammation, immunodeficiency 114, folate-responsive, immunodeficiency 115 with autoinflammation, immunodeficiency 117, immunodeficiency 118, immunodeficiency 119, immunodeficiency 121 with autoinflammation, immunodeficiency 122, immunodeficiency 123 with HPV-related verrucosis, immunodeficiency 125, immunodeficiency 126, susceptibility to, immunodeficiency 127, immunodeficiency 128, immunodeficiency 132b, immunodeficiency 133 with ectodermal dysplasia with or without peripheral neuropathy, immunodeficiency 134 (Epstein-Barr virus-specific)

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

22 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 4 benign, 4 likely benign, 3 pathogenic, 2 likely pathogenic, 1 conflicting classifications of pathogenicity, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1064710	NM_005026.5(PIK3CD):c.1654del (p.Val552fs)	PIK3CD	Pathogenic	no assertion criteria provided
1064711	NM_005026.5(PIK3CD):c.2558_2559del (p.Asp853fs)	PIK3CD	Pathogenic	no assertion criteria provided
88675	NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)	PIK3CD	Pathogenic	reviewed by expert panel
2582528	NM_005026.5(PIK3CD):c.266_273del (p.Leu89fs)	PIK3CD	Likely pathogenic	criteria provided, single submitter
3237514	NM_005026.5(PIK3CD):c.317dup (p.Asp107fs)	PIK3CD	Likely pathogenic	criteria provided, single submitter
1135386	NM_005026.5(PIK3CD):c.171G>T (p.Pro57=)	PIK3CD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
651966	NM_005026.5(PIK3CD):c.1242G>A (p.Ala414=)	LOC126805612	Uncertain significance	criteria provided, multiple submitters, no conflicts
1359338	NM_005026.5(PIK3CD):c.58G>A (p.Val20Ile)	PIK3CD	Uncertain significance	criteria provided, multiple submitters, no conflicts
373411	NM_005026.5(PIK3CD):c.3029A>C (p.Glu1010Ala)	PIK3CD	Uncertain significance	criteria provided, multiple submitters, no conflicts
643256	NM_005026.5(PIK3CD):c.1955+5C>T	PIK3CD	Uncertain significance	criteria provided, multiple submitters, no conflicts
662314	NM_005026.5(PIK3CD):c.2997G>A (p.Lys999=)	PIK3CD	Uncertain significance	criteria provided, multiple submitters, no conflicts
806050	NM_005026.5(PIK3CD):c.1642C>T (p.Arg548Trp)	PIK3CD	Uncertain significance	reviewed by expert panel
969000	NM_005026.5(PIK3CD):c.1339+4G>A	PIK3CD	Uncertain significance	criteria provided, multiple submitters, no conflicts
709503	NM_005026.5(PIK3CD):c.1394C>T (p.Thr465Met)	LOC126805612	Benign	reviewed by expert panel
941354	NM_005026.5(PIK3CD):c.1459G>A (p.Ala487Thr)	LOC126805612	Likely benign	reviewed by expert panel
1227097	NM_005026.5(PIK3CD):c.2348-30C>T	PIK3CD	Benign	criteria provided, multiple submitters, no conflicts
424409	NM_005026.5(PIK3CD):c.1777G>C (p.Gly593Arg)	PIK3CD	Likely benign	reviewed by expert panel
474022	NM_005026.5(PIK3CD):c.1005C>T (p.Ala335=)	PIK3CD	Benign	criteria provided, multiple submitters, no conflicts
474028	NM_005026.5(PIK3CD):c.2919C>T (p.Leu973=)	PIK3CD	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
642308	NM_005026.5(PIK3CD):c.598G>A (p.Glu200Lys)	PIK3CD	Likely benign	reviewed by expert panel
736478	NM_005026.5(PIK3CD):c.2997+10G>A	PIK3CD	Likely benign	criteria provided, multiple submitters, no conflicts
811566	NM_005026.5(PIK3CD):c.2808C>T (p.Tyr936=)	PIK3CD	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PIK3CD	Definitive	Autosomal dominant	immunodeficiency 14	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PIK3CD	Orphanet:221139	Combined immunodeficiency with facio-oculo-skeletal anomalies
PIK3CD	Orphanet:33110	Autosomal non-syndromic agammaglobulinemia
PIK3CD	Orphanet:693661	Activated PI3K-delta syndrome 1

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PIK3CD	HGNC:8977	ENSG00000171608	O00329	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PIK3CD	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform	Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PIK3CD	Kinase	yes	2.7.1.137	PI3K_Ras-bd_dom, PI3/4_kinase_cat_dom, PI3K_accessory_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	1
granulocyte	1
lymph node	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PIK3CD	253	ubiquitous	marker	granulocyte, blood, lymph node

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PIK3CD	2,059

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PIK3CD	O00329	18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Co-stimulation by ICOS	1	1038.2×	0.006	PIK3CD
Erythropoietin activates Phosphoinositide-3-kinase (PI3K)	1	951.7×	0.006	PIK3CD
Regulation of signaling by CBL	1	496.5×	0.006	PIK3CD
Interleukin receptor SHC signaling	1	407.9×	0.006	PIK3CD
CD28 dependent PI3K/Akt signaling	1	393.8×	0.006	PIK3CD
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	1	356.9×	0.006	PIK3CD
Signaling by CSF1 (M-CSF) in myeloid cells	1	346.1×	0.006	PIK3CD
Interleukin-3, Interleukin-5 and GM-CSF signaling	1	317.2×	0.006	PIK3CD
RET signaling	1	259.6×	0.006	PIK3CD
Synthesis of PIPs at the plasma membrane	1	211.5×	0.007	PIK3CD
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	160.8×	0.008	PIK3CD
Constitutive Signaling by Aberrant PI3K in Cancer	1	126.9×	0.009	PIK3CD
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	96.8×	0.011	PIK3CD
PIP3 activates AKT signaling	1	66.8×	0.015	PIK3CD

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
natural killer cell chemotaxis	1	8426.0×	0.002	PIK3CD
mast cell chemotaxis	1	4213.0×	0.002	PIK3CD
respiratory burst involved in defense response	1	4213.0×	0.002	PIK3CD
mast cell differentiation	1	4213.0×	0.002	PIK3CD
positive regulation of neutrophil apoptotic process	1	3370.4×	0.002	PIK3CD
B cell chemotaxis	1	2808.7×	0.002	PIK3CD
neutrophil extravasation	1	2808.7×	0.002	PIK3CD
positive regulation of epithelial tube formation	1	2808.7×	0.002	PIK3CD
phosphatidylinositol-3-phosphate biosynthetic process	1	1296.3×	0.003	PIK3CD
T cell chemotaxis	1	1123.5×	0.003	PIK3CD
vascular endothelial growth factor signaling pathway	1	1053.2×	0.003	PIK3CD
natural killer cell differentiation	1	887.0×	0.003	PIK3CD
phosphatidylinositol-mediated signaling	1	702.2×	0.004	PIK3CD
mast cell degranulation	1	624.1×	0.004	PIK3CD
natural killer cell activation	1	581.1×	0.004	PIK3CD
B cell activation	1	455.5×	0.005	PIK3CD
B cell receptor signaling pathway	1	401.2×	0.005	PIK3CD
T cell differentiation	1	383.0×	0.005	PIK3CD
T cell costimulation	1	374.5×	0.005	PIK3CD
neutrophil chemotaxis	1	285.6×	0.006	PIK3CD
positive regulation of cytokine production	1	271.8×	0.006	PIK3CD
T cell activation	1	259.3×	0.006	PIK3CD
positive regulation of endothelial cell migration	1	251.5×	0.006	PIK3CD
positive regulation of endothelial cell proliferation	1	230.8×	0.007	PIK3CD
B cell differentiation	1	218.9×	0.007	PIK3CD
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	210.7×	0.007	PIK3CD
T cell receptor signaling pathway	1	151.8×	0.009	PIK3CD
positive regulation of angiogenesis	1	115.4×	0.011	PIK3CD
adaptive immune response	1	84.3×	0.015	PIK3CD
protein phosphorylation	1	68.0×	0.018	PIK3CD

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PIK3CD	IDELALISIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIK3CD	66	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IDELALISIB	4	PIK3CD
ALPELISIB	4	PIK3CD
DUVELISIB	4	PIK3CD
COPANLISIB	4	PIK3CD
UMBRALISIB	4	PIK3CD
CAFFEINE	4	PIK3CD
THEOPHYLLINE	4	PIK3CD
COPANLISIB HYDROCHLORIDE	4	PIK3CD
LENIOLISIB	4	PIK3CD
INAVOLISIB	4	PIK3CD
SUNITINIB	4	PIK3CD
DASATINIB	4	PIK3CD
DACTOLISIB	3	PIK3CD
BUPARLISIB	3	PIK3CD
TASELISIB	3	PIK3CD
PARSACLISIB	3	PIK3CD
POVORCITINIB	3	PIK3CD
GEDATOLISIB	3	PIK3CD
LESTAURTINIB	3	PIK3CD
OMIPALISIB	2	PIK3CD
GSK-2636771	2	PIK3CD
FIMEPINOSTAT	2	PIK3CD
EGANELISIB	2	PIK3CD
AMDIZALISIB	2	PIK3CD
RISOVALISIB	2	PIK3CD
PICTILISIB	2	PIK3CD
ZSTK-474	2	PIK3CD
PF-04691502	2	PIK3CD
IZORLISIB	2	PIK3CD
APITOLISIB	2	PIK3CD

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PIK3CD	1,111	Binding:1094, ADMET:8, Functional:8, Toxicity:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PIK3CD	2.7.1.137, 2.7.1.153, 2.7.11.1	phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PIK3CD	1,111

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
IDELALISIB	4	PIK3CD
ALPELISIB	4	PIK3CD
DUVELISIB	4	PIK3CD
COPANLISIB	4	PIK3CD
UMBRALISIB	4	PIK3CD
CAFFEINE	4	PIK3CD
THEOPHYLLINE	4	PIK3CD
COPANLISIB HYDROCHLORIDE	4	PIK3CD
LENIOLISIB	4	PIK3CD
INAVOLISIB	4	PIK3CD
SUNITINIB	4	PIK3CD
DASATINIB	4	PIK3CD
DACTOLISIB	3	PIK3CD
BUPARLISIB	3	PIK3CD
TASELISIB	3	PIK3CD
PARSACLISIB	3	PIK3CD
POVORCITINIB	3	PIK3CD
GEDATOLISIB	3	PIK3CD
LESTAURTINIB	3	PIK3CD
OMIPALISIB	2	PIK3CD
GSK-2636771	2	PIK3CD
FIMEPINOSTAT	2	PIK3CD
EGANELISIB	2	PIK3CD
AMDIZALISIB	2	PIK3CD
RISOVALISIB	2	PIK3CD
PICTILISIB	2	PIK3CD
ZSTK-474	2	PIK3CD
PF-04691502	2	PIK3CD
IZORLISIB	2	PIK3CD
APITOLISIB	2	PIK3CD

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PIK3CD
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.