Immunodeficiency 14

Summary

Immunodeficiency 14 (MONDO:0014222) is a disease caused by PIK3CD (GenCC Definitive), with 4 cohort genes. The dominant Reactome pathway is CD28 dependent PI3K/Akt signaling (3 cohort genes).

At a glance

• Causal gene: PIK3CD (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 953
• Phenotypes (HPO): 22

Clinical features

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0002205	Recurrent respiratory infections	Very frequent (80-99%)
HP:0001744	Splenomegaly	Frequent (30-79%)
HP:0002110	Bronchiectasis	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0002716	Lymphadenopathy	Frequent (30-79%)
HP:0002960	Autoimmunity	Frequent (30-79%)
HP:0010976	Decreased total B cell count	Frequent (30-79%)
HP:0011956	Intestinal lymphoid nodular hyperplasia	Frequent (30-79%)
HP:0000509	Conjunctivitis	Occasional (5-29%)
HP:0000620	Dacryocystitis	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0002014	Diarrhea	Occasional (5-29%)
HP:0002024	Malabsorption	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0005401	Recurrent candida infections	Occasional (5-29%)
HP:0011110	Recurrent tonsillitis	Occasional (5-29%)
HP:0020114	Persistent human papillomavirus infection	Occasional (5-29%)
HP:0032163	Molluscum contagiosum	Occasional (5-29%)
HP:0032204	Chronic active Epstein-Barr virus infection	Occasional (5-29%)
HP:0032247	Persistent CMV viremia	Occasional (5-29%)
HP:0200043	Verrucae	Occasional (5-29%)
HP:0031699	Disseminated cryptosporidium infection	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency 14
Mondo ID	MONDO:0014222
OMIM	615513
Orphanet	693661
DOID	DOID:0111936
UMLS	C3714976
MedGen	811535
GARD	0015979
NORD	111933
Is cancer (heuristic)	no

Also known as: Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) · IMD14 · immunodeficiency 14 · immunodeficiency 14A, autosomal dominant · immunodeficiency type 14

Data availability: 953 ClinVar variants · 54 ClinGen variant curations · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › B cell deficiency › agammaglobulinemia › activated PI3K-delta syndrome › immunodeficiency 14

Related subtypes (1): immunodeficiency 36 with lymphoproliferation

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

600 retrieved; paginated sample, class counts are floors:

346 likely benign, 210 uncertain significance, 22 benign, 9 pathogenic, 5 likely pathogenic, 4 conflicting classifications of pathogenicity, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2758361	NM_005026.5(PIK3CD):c.1306G>T (p.Glu436Ter)	LOC126805612	Pathogenic	criteria provided, single submitter
132807	NM_005026.5(PIK3CD):c.1573G>A (p.Glu525Lys)	PIK3CD	Pathogenic	reviewed by expert panel
1500652	NM_005026.5(PIK3CD):c.171_178del (p.Leu58fs)	PIK3CD	Pathogenic	criteria provided, single submitter
2077526	NM_005026.5(PIK3CD):c.767dup (p.Cys257fs)	PIK3CD	Pathogenic	criteria provided, single submitter
2699590	NM_005026.5(PIK3CD):c.2164G>T (p.Glu722Ter)	PIK3CD	Pathogenic	criteria provided, single submitter
2810787	NM_005026.5(PIK3CD):c.1687C>T (p.Gln563Ter)	PIK3CD	Pathogenic	criteria provided, single submitter
2845778	NM_005026.5(PIK3CD):c.494_512del (p.Tyr165fs)	PIK3CD	Pathogenic	criteria provided, single submitter
2849187	NM_005026.5(PIK3CD):c.104_105del (p.Pro35fs)	PIK3CD	Pathogenic	criteria provided, single submitter
2849820	NM_005026.5(PIK3CD):c.2704C>T (p.Arg902Ter)	PIK3CD	Pathogenic	criteria provided, single submitter
132806	NM_005026.5(PIK3CD):c.1002C>A (p.Asn334Lys)	PIK3CD	Likely pathogenic	reviewed by expert panel
132808	NM_005026.5(PIK3CD):c.1246T>C (p.Cys416Arg)	PIK3CD	Likely pathogenic	reviewed by expert panel
1406866	NM_005026.5(PIK3CD):c.1570T>A (p.Tyr524Asn)	PIK3CD	Likely pathogenic	reviewed by expert panel
1457684	NM_005026.5(PIK3CD):c.1571A>C (p.Tyr524Ser)	PIK3CD	Likely pathogenic	reviewed by expert panel
2733822	NM_005026.5(PIK3CD):c.371G>A (p.Gly124Asp)	PIK3CD	Likely pathogenic	reviewed by expert panel
1032967	NM_005026.5(PIK3CD):c.1955+15C>T	PIK3CD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1044679	NM_005026.5(PIK3CD):c.2489G>A (p.Arg830His)	PIK3CD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1135386	NM_005026.5(PIK3CD):c.171G>T (p.Pro57=)	PIK3CD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1352150	NM_005026.5(PIK3CD):c.62T>C (p.Val21Ala)	PIK3CD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1011802	NM_005026.5(PIK3CD):c.1070C>T (p.Thr357Met)	LOC126805612	Uncertain significance	criteria provided, multiple submitters, no conflicts
1024241	NM_005026.5(PIK3CD):c.1072G>C (p.Val358Leu)	LOC126805612	Uncertain significance	criteria provided, single submitter
1032966	NM_005026.5(PIK3CD):c.1435G>A (p.Ala479Thr)	LOC126805612	Uncertain significance	criteria provided, single submitter
1407956	NM_005026.5(PIK3CD):c.1085A>T (p.Glu362Val)	LOC126805612	Uncertain significance	criteria provided, single submitter
1409092	NM_005026.5(PIK3CD):c.1214G>A (p.Arg405His)	LOC126805612	Uncertain significance	reviewed by expert panel
1435006	NM_005026.5(PIK3CD):c.1353G>C (p.Glu451Asp)	LOC126805612	Uncertain significance	criteria provided, multiple submitters, no conflicts
1445160	NM_005026.5(PIK3CD):c.1333G>A (p.Val445Ile)	LOC126805612	Uncertain significance	criteria provided, single submitter
1495102	NM_005026.5(PIK3CD):c.1057A>G (p.Met353Val)	LOC126805612	Uncertain significance	criteria provided, single submitter
1499033	NM_005026.5(PIK3CD):c.1439C>T (p.Pro480Leu)	LOC126805612	Uncertain significance	criteria provided, single submitter
1996640	NM_005026.5(PIK3CD):c.1442A>C (p.His481Pro)	LOC126805612	Uncertain significance	criteria provided, single submitter
1998252	NM_005026.5(PIK3CD):c.1344G>C (p.Glu448Asp)	LOC126805612	Uncertain significance	criteria provided, single submitter
2052886	NM_005026.5(PIK3CD):c.1165C>T (p.Arg389Cys)	LOC126805612	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 10 · 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
MTOR	Orphanet:269001	Isolated focal cortical dysplasia type IIa
MTOR	Orphanet:269008	Isolated focal cortical dysplasia type IIb
MTOR	Orphanet:457485	Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome
MTOR	Orphanet:99802	Hemimegalencephaly
PIK3R1	Orphanet:3163	SHORT syndrome
PIK3R1	Orphanet:33110	Autosomal non-syndromic agammaglobulinemia
PIK3R1	Orphanet:693681	Activated PI3K-delta syndrome 2

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

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
CORT	HGNC:2257	ENSG00000241563	O00230	Cortistatin	clinvar
MTOR	HGNC:3942	ENSG00000198793	P42345	Serine/threonine-protein kinase mTOR	clinvar
PIK3R1	HGNC:8979	ENSG00000145675	P27986	Phosphatidylinositol 3-kinase regulatory subunit alpha	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.
CORT	Cortistatin	Precursor of neuropeptides that bind to all somatostatin receptor (SSTR) subtypes.
MTOR	Serine/threonine-protein kinase mTOR	Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals.
PIK3R1	Phosphatidylinositol 3-kinase regulatory subunit alpha	Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.75

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	3	20.8×	4e-04
Other/Unknown	1	0.5×	0.962

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
CORT	Other/Unknown	no		Somatostatin, Somatostatin/Cortistatin_C
MTOR	Kinase	yes		PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom
PIK3R1	Kinase	yes	2.7.1.153	RhoGAP_dom, SH2, SH3_domain

Expression context

Cohort genes with no expression data: 0.

4 cohort genes 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	1
granulocyte	1
lymph node	1
caudate nucleus	1
prefrontal cortex	1
putamen	1
cerebellar hemisphere	1
primordial germ cell in gonad	1
right hemisphere of cerebellum	1
calcaneal tendon	1
caput epididymis	1
corpus epididymis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PIK3CD	253	ubiquitous	marker	granulocyte, blood, lymph node
CORT	130	tissue_specific	marker	putamen, caudate nucleus, prefrontal cortex
MTOR	207	ubiquitous	marker	primordial germ cell in gonad, right hemisphere of cerebellum, cerebellar hemisphere
PIK3R1	294	ubiquitous	marker	calcaneal tendon, caput epididymis, corpus epididymis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MTOR	9,490
PIK3R1	5,168
PIK3CD	2,059
CORT	945

Intra-cohort edges

A	B	Sources
PIK3CD	PIK3R1	biogrid_interaction, intact, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PIK3R1	P27986	105
MTOR	P42345	70
PIK3CD	O00329	18
CORT	O00230	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 118. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
CD28 dependent PI3K/Akt signaling	3	295.3×	7e-06	PIK3CD, MTOR, PIK3R1
Co-stimulation by ICOS	2	519.1×	2e-04	PIK3CD, PIK3R1
Erythropoietin activates Phosphoinositide-3-kinase (PI3K)	2	475.8×	2e-04	PIK3CD, PIK3R1
PIP3 activates AKT signaling	3	50.1×	4e-04	PIK3CD, MTOR, PIK3R1
Regulation of signaling by CBL	2	248.3×	5e-04	PIK3CD, PIK3R1
Interleukin receptor SHC signaling	2	203.9×	7e-04	PIK3CD, PIK3R1
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	2	178.4×	7e-04	PIK3CD, PIK3R1
Signaling by CSF1 (M-CSF) in myeloid cells	2	173.0×	7e-04	PIK3CD, PIK3R1
Interleukin-3, Interleukin-5 and GM-CSF signaling	2	158.6×	8e-04	PIK3CD, PIK3R1
RET signaling	2	129.8×	0.001	PIK3CD, PIK3R1
Synthesis of PIPs at the plasma membrane	2	105.7×	0.001	PIK3CD, PIK3R1
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	2	80.4×	0.002	PIK3CD, MTOR
VEGFA-VEGFR2 Pathway	2	69.6×	0.003	MTOR, PIK3R1
Constitutive Signaling by Aberrant PI3K in Cancer	2	63.4×	0.003	PIK3CD, PIK3R1
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	2	48.4×	0.005	PIK3CD, PIK3R1
MET activates PI3K/AKT signaling	1	475.8×	0.015	PIK3R1
Activated NTRK3 signals through PI3K	1	475.8×	0.015	PIK3R1
Activated NTRK2 signals through PI3K	1	407.9×	0.015	PIK3R1
Signaling by LTK in cancer	1	407.9×	0.015	PIK3R1
PI3K/AKT activation	1	317.2×	0.019	PIK3R1
IRS-mediated signalling	1	259.6×	0.020	PIK3R1
PI3K events in ERBB4 signaling	1	259.6×	0.020	PIK3R1
GP1b-IX-V activation signalling	1	237.9×	0.020	PIK3R1
Signaling by FGFR4 in disease	1	237.9×	0.020	PIK3R1
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	1	219.6×	0.020	PIK3R1
Signaling by PDGFRA extracellular domain mutants	1	219.6×	0.020	PIK3R1
Signaling by LTK	1	219.6×	0.020	PIK3R1
Signaling by FLT3 ITD and TKD mutants	1	190.3×	0.020	PIK3R1
Constitutive Signaling by EGFRvIII	1	178.4×	0.020	PIK3R1
Dengue virus modulates apoptosis	1	178.4×	0.020	MTOR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of lamellipodium assembly	2	300.9×	0.002	MTOR, PIK3R1
T cell differentiation	2	191.5×	0.002	PIK3CD, PIK3R1
T cell costimulation	2	187.2×	0.002	PIK3CD, MTOR
B cell differentiation	2	109.4×	0.004	PIK3CD, PIK3R1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	2	105.3×	0.004	PIK3CD, PIK3R1
cellular response to insulin stimulus	2	85.1×	0.005	MTOR, PIK3R1
positive regulation of SCF-dependent proteasomal ubiquitin-dependent catabolic process	1	4213.0×	0.005	MTOR
natural killer cell chemotaxis	1	2106.5×	0.007	PIK3CD
regulation of locomotor rhythm	1	2106.5×	0.007	MTOR
positive regulation of cytoplasmic translational initiation	1	2106.5×	0.007	MTOR
regulation of toll-like receptor 4 signaling pathway	1	1404.3×	0.007	PIK3R1
positive regulation of endoplasmic reticulum unfolded protein response	1	1404.3×	0.007	PIK3R1
T-helper 1 cell lineage commitment	1	1053.2×	0.007	MTOR
mast cell chemotaxis	1	1053.2×	0.007	PIK3CD
respiratory burst involved in defense response	1	1053.2×	0.007	PIK3CD
mast cell differentiation	1	1053.2×	0.007	PIK3CD
myeloid leukocyte migration	1	1053.2×	0.007	PIK3R1
negative regulation of lysosome organization	1	1053.2×	0.007	MTOR
positive regulation of pentose-phosphate shunt	1	1053.2×	0.007	MTOR
positive regulation of neutrophil apoptotic process	1	842.6×	0.007	PIK3CD
cellular response to methionine	1	842.6×	0.007	MTOR
positive regulation of wound healing, spreading of epidermal cells	1	842.6×	0.007	MTOR
‘de novo’ pyrimidine nucleobase biosynthetic process	1	702.2×	0.007	MTOR
interleukin-18-mediated signaling pathway	1	702.2×	0.007	PIK3R1
B cell chemotaxis	1	702.2×	0.007	PIK3CD
voluntary musculoskeletal movement	1	702.2×	0.007	MTOR
neutrophil extravasation	1	702.2×	0.007	PIK3CD
positive regulation of epithelial tube formation	1	702.2×	0.007	PIK3CD
regulation of lysosome organization	1	702.2×	0.007	MTOR
protein stabilization	2	33.4×	0.007	MTOR, PIK3R1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) 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
MTOR	SALMETEROL XINAFOATE
PIK3R1	IDELALISIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MTOR	164	4
PIK3CD	66	4
PIK3R1	26	4
CORT	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IDELALISIB	4	PIK3CD, PIK3R1
ALPELISIB	4	MTOR, PIK3CD, PIK3R1
DUVELISIB	4	PIK3CD, PIK3R1
COPANLISIB	4	MTOR, PIK3CD, PIK3R1
UMBRALISIB	4	PIK3CD, PIK3R1
CAFFEINE	4	PIK3CD
THEOPHYLLINE	4	PIK3CD
COPANLISIB HYDROCHLORIDE	4	PIK3CD
LENIOLISIB	4	PIK3CD
INAVOLISIB	4	PIK3CD
SUNITINIB	4	PIK3CD
DASATINIB	4	MTOR, PIK3CD
SALMETEROL XINAFOATE	4	MTOR
IMIPRAMINE	4	MTOR
AMOXAPINE	4	MTOR
IDARUBICIN	4	MTOR
TETRABENAZINE	4	MTOR
TEMSIROLIMUS	4	MTOR
MIFEPRISTONE	4	MTOR
ZIPRASIDONE HYDROCHLORIDE	4	MTOR
PIMOZIDE	4	MTOR
NAFTOPIDIL	4	MTOR
NICLOSAMIDE	4	MTOR
FELODIPINE	4	MTOR
NICARDIPINE	4	MTOR
AZACITIDINE	4	MTOR
TRIFLUPERIDOL	4	MTOR
CYCLOSPORINE	4	MTOR
CLEMASTINE	4	MTOR
TERFENADINE	4	MTOR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
MTOR	1,375	Binding:1335, Functional:37, ADMET:2, Toxicity:1
PIK3CD	1,111	Binding:1094, ADMET:8, Functional:8, Toxicity:1
PIK3R1	493	Binding:470, ADMET:23

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
PIK3R1	2.7.1.153	phosphatidylinositol-4,5-bisphosphate 3-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
MTOR	1,375
PIK3R1	493

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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, PIK3R1
ALPELISIB	4	MTOR, PIK3CD, PIK3R1
DUVELISIB	4	PIK3CD, PIK3R1
COPANLISIB	4	MTOR, PIK3CD, PIK3R1
UMBRALISIB	4	PIK3CD, PIK3R1
CAFFEINE	4	PIK3CD
THEOPHYLLINE	4	PIK3CD
COPANLISIB HYDROCHLORIDE	4	PIK3CD
LENIOLISIB	4	PIK3CD
INAVOLISIB	4	PIK3CD
SUNITINIB	4	PIK3CD
DASATINIB	4	MTOR, PIK3CD
SALMETEROL XINAFOATE	4	MTOR
IMIPRAMINE	4	MTOR
AMOXAPINE	4	MTOR
IDARUBICIN	4	MTOR
TETRABENAZINE	4	MTOR
TEMSIROLIMUS	4	MTOR
MIFEPRISTONE	4	MTOR
ZIPRASIDONE HYDROCHLORIDE	4	MTOR
PIMOZIDE	4	MTOR
NAFTOPIDIL	4	MTOR
NICLOSAMIDE	4	MTOR
FELODIPINE	4	MTOR
NICARDIPINE	4	MTOR
AZACITIDINE	4	MTOR
TRIFLUPERIDOL	4	MTOR
CYCLOSPORINE	4	MTOR
CLEMASTINE	4	MTOR
TERFENADINE	4	MTOR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	PIK3CD, MTOR, PIK3R1
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	1	CORT

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CORT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.