Immunodeficiency 36 with lymphoproliferation

Summary

Immunodeficiency 36 with lymphoproliferation (MONDO:0014453) is a disease caused by PIK3R1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: PIK3R1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 541
• Phenotypes (HPO): 21

Clinical features

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001744	Splenomegaly	Frequent (30-79%)
HP:0002110	Bronchiectasis	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0002716	Lymphadenopathy	Frequent (30-79%)
HP:0002720	Decreased circulating IgA level	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0005387	Combined immunodeficiency	Frequent (30-79%)
HP:0008348	Decreased circulating IgG2 level	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:0002014	Diarrhea	Occasional (5-29%)
HP:0002024	Malabsorption	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0002960	Autoimmunity	Occasional (5-29%)
HP:0005411	Chronic intestinal candidiasis	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%)

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency 36 with lymphoproliferation
Mondo ID	MONDO:0014453
OMIM	616005
Orphanet	693681
DOID	DOID:0111949
UMLS	C4014934
MedGen	863371
GARD	0016046
Is cancer (heuristic)	no

Also known as: activated PI3K-delta syndrome-2 · APDS2 · IMD36 · immunodeficiency 36 · immunodeficiency type 36

Data availability: 541 ClinVar variants · 2 GenCC gene-disease records · 1 cell line.

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 36 with lymphoproliferation

Related subtypes (1): immunodeficiency 14

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

541 retrieved; paginated sample, class counts are floors:

256 uncertain significance, 215 likely benign, 26 pathogenic, 14 benign/likely benign, 12 conflicting classifications of pathogenicity, 6 benign, 6 likely pathogenic, 5 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1072261	NM_181523.3(PIK3R1):c.901C>T (p.Arg301Ter)	PIK3R1	Pathogenic	criteria provided, multiple submitters, no conflicts
1370470	NM_181523.3(PIK3R1):c.484C>T (p.Arg162Ter)	PIK3R1	Pathogenic	criteria provided, single submitter
1393351	NM_181523.3(PIK3R1):c.1344dup (p.Leu449fs)	PIK3R1	Pathogenic	criteria provided, single submitter
1452339	NM_181523.3(PIK3R1):c.450C>G (p.Tyr150Ter)	PIK3R1	Pathogenic	criteria provided, single submitter
156008	NM_181523.3(PIK3R1):c.1425+1G>T	PIK3R1	Pathogenic	criteria provided, multiple submitters, no conflicts
156009	NM_181523.3(PIK3R1):c.1425+1G>C	PIK3R1	Pathogenic	criteria provided, multiple submitters, no conflicts
2104788	NM_181523.3(PIK3R1):c.1350_1360del (p.Glu451fs)	PIK3R1	Pathogenic	criteria provided, single submitter
2126685	NM_181523.3(PIK3R1):c.1072C>T (p.Arg358Ter)	PIK3R1	Pathogenic	criteria provided, single submitter
2951379	NM_181523.3(PIK3R1):c.1650_1674del (p.Lys551fs)	PIK3R1	Pathogenic	criteria provided, single submitter
2952024	NM_181523.3(PIK3R1):c.1314_1317del (p.Glu439fs)	PIK3R1	Pathogenic	criteria provided, single submitter
2952766	NM_181523.3(PIK3R1):c.1306_1313del (p.Val436fs)	PIK3R1	Pathogenic	criteria provided, single submitter
372467	NM_181523.3(PIK3R1):c.1425+1G>A	PIK3R1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3748560	NM_181523.3(PIK3R1):c.1156C>T (p.Arg386Ter)	PIK3R1	Pathogenic	criteria provided, single submitter
376258	NM_181523.3(PIK3R1):c.1381C>T (p.Arg461Ter)	PIK3R1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3897534	PIK3R1, 38-BP DEL, IVS10AS	PIK3R1	Pathogenic	no assertion criteria provided
3901222	NM_181523.3(PIK3R1):c.703C>T (p.Gln235Ter)	PIK3R1	Pathogenic	criteria provided, single submitter
446497	NM_181523.3(PIK3R1):c.1425+2T>A	PIK3R1	Pathogenic	criteria provided, multiple submitters, no conflicts
446498	NM_181523.3(PIK3R1):c.1425+2T>G	PIK3R1	Pathogenic	criteria provided, multiple submitters, no conflicts
446499	NM_181523.3(PIK3R1):c.1425+2_1425+3del	PIK3R1	Pathogenic	no assertion criteria provided
446500	NM_181523.3(PIK3R1):c.1300-1G>C	PIK3R1	Pathogenic	no assertion criteria provided
4785500	NM_181523.3(PIK3R1):c.1756C>T (p.Gln586Ter)	PIK3R1	Pathogenic	criteria provided, single submitter
4787131	NM_181523.3(PIK3R1):c.521del (p.Leu174fs)	PIK3R1	Pathogenic	criteria provided, single submitter
4791512	NM_181523.3(PIK3R1):c.1600C>T (p.Arg534Ter)	PIK3R1	Pathogenic	criteria provided, single submitter
4791940	NM_181523.3(PIK3R1):c.1960C>T (p.Gln654Ter)	PIK3R1	Pathogenic	criteria provided, single submitter
48646	NM_181523.3(PIK3R1):c.893G>A (p.Trp298Ter)	PIK3R1	Pathogenic	criteria provided, single submitter
571336	NM_181523.3(PIK3R1):c.1710dup (p.Ile571fs)	PIK3R1	Pathogenic	criteria provided, single submitter
60763	NM_181523.3(PIK3R1):c.1945C>T (p.Arg649Trp)	PIK3R1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
648899	NM_181523.3(PIK3R1):c.965del (p.Met322fs)	PIK3R1	Pathogenic	criteria provided, single submitter
827732	NM_181523.3(PIK3R1):c.1300-2A>G	PIK3R1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
982699	NM_181523.3(PIK3R1):c.661C>T (p.Gln221Ter)	PIK3R1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · 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
PIK3R1	Definitive	Autosomal dominant	immunodeficiency 36 with lymphoproliferation	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PIK3R1	Orphanet:3163	SHORT syndrome
PIK3R1	Orphanet:33110	Autosomal non-syndromic agammaglobulinemia
PIK3R1	Orphanet:693681	Activated PI3K-delta syndrome 2

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
PIK3R1	HGNC:8979	ENSG00000145675	P27986	Phosphatidylinositol 3-kinase regulatory subunit alpha	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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: 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)
PIK3R1	Kinase	yes	2.7.1.153	RhoGAP_dom, SH2, SH3_domain

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
calcaneal tendon	1
caput epididymis	1
corpus epididymis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PIK3R1	294	ubiquitous	marker	calcaneal tendon, caput epididymis, corpus epididymis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PIK3R1	5,168

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PIK3R1	P27986	105

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 78. 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
MET activates PI3K/AKT signaling	1	1903.3×	0.005	PIK3R1
Activated NTRK3 signals through PI3K	1	1903.3×	0.005	PIK3R1
Activated NTRK2 signals through PI3K	1	1631.4×	0.005	PIK3R1
Signaling by LTK in cancer	1	1631.4×	0.005	PIK3R1
PI3K/AKT activation	1	1268.9×	0.005	PIK3R1
IRS-mediated signalling	1	1038.2×	0.005	PIK3R1
PI3K events in ERBB4 signaling	1	1038.2×	0.005	PIK3R1
Co-stimulation by ICOS	1	1038.2×	0.005	PIK3R1
GP1b-IX-V activation signalling	1	951.7×	0.005	PIK3R1
Signaling by FGFR4 in disease	1	951.7×	0.005	PIK3R1
Erythropoietin activates Phosphoinositide-3-kinase (PI3K)	1	951.7×	0.005	PIK3R1
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	1	878.5×	0.005	PIK3R1
Signaling by PDGFRA extracellular domain mutants	1	878.5×	0.005	PIK3R1
Signaling by LTK	1	878.5×	0.005	PIK3R1
Signaling by FLT3 ITD and TKD mutants	1	761.3×	0.005	PIK3R1
Constitutive Signaling by EGFRvIII	1	713.8×	0.005	PIK3R1
PI3K events in ERBB2 signaling	1	671.8×	0.005	PIK3R1
Signaling by ERBB2 ECD mutants	1	671.8×	0.005	PIK3R1
GAB1 signalosome	1	634.4×	0.005	PIK3R1
Signaling by cytosolic FGFR1 fusion mutants	1	634.4×	0.005	PIK3R1
PI-3K cascade:FGFR3	1	634.4×	0.005	PIK3R1
Tie2 Signaling	1	601.0×	0.005	PIK3R1
Role of LAT2/NTAL/LAB on calcium mobilization	1	601.0×	0.005	PIK3R1
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	1	571.0×	0.005	PIK3R1
Signaling by ALK	1	571.0×	0.005	PIK3R1
PI-3K cascade:FGFR4	1	571.0×	0.005	PIK3R1
Signaling by FLT3 fusion proteins	1	571.0×	0.005	PIK3R1
PI-3K cascade:FGFR1	1	519.1×	0.005	PIK3R1
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	1	519.1×	0.005	PIK3R1
PI-3K cascade:FGFR2	1	496.5×	0.005	PIK3R1

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
regulation of toll-like receptor 4 signaling pathway	1	5617.3×	0.003	PIK3R1
positive regulation of endoplasmic reticulum unfolded protein response	1	5617.3×	0.003	PIK3R1
myeloid leukocyte migration	1	4213.0×	0.003	PIK3R1
interleukin-18-mediated signaling pathway	1	2808.7×	0.004	PIK3R1
positive regulation of focal adhesion disassembly	1	1872.4×	0.004	PIK3R1
T follicular helper cell differentiation	1	1404.3×	0.005	PIK3R1
growth hormone receptor signaling pathway	1	1203.7×	0.005	PIK3R1
positive regulation of RNA splicing	1	1053.2×	0.005	PIK3R1
positive regulation of leukocyte migration	1	991.3×	0.005	PIK3R1
negative regulation of cell-matrix adhesion	1	887.0×	0.005	PIK3R1
positive regulation of lamellipodium assembly	1	601.9×	0.005	PIK3R1
intracellular glucose homeostasis	1	581.1×	0.005	PIK3R1
negative regulation of stress fiber assembly	1	581.1×	0.005	PIK3R1
positive regulation of filopodium assembly	1	561.7×	0.005	PIK3R1
negative regulation of osteoclast differentiation	1	543.6×	0.005	PIK3R1
insulin-like growth factor receptor signaling pathway	1	495.6×	0.005	PIK3R1
phosphatidylinositol phosphate biosynthetic process	1	481.5×	0.005	PIK3R1
positive regulation of D-glucose import across plasma membrane	1	455.5×	0.005	PIK3R1
natural killer cell mediated cytotoxicity	1	432.1×	0.005	PIK3R1
positive regulation of protein import into nucleus	1	421.3×	0.005	PIK3R1
extrinsic apoptotic signaling pathway via death domain receptors	1	401.2×	0.005	PIK3R1
T cell differentiation	1	383.0×	0.005	PIK3R1
osteoclast differentiation	1	343.9×	0.005	PIK3R1
substrate adhesion-dependent cell spreading	1	343.9×	0.005	PIK3R1
positive regulation of smooth muscle cell proliferation	1	330.4×	0.005	PIK3R1
intrinsic apoptotic signaling pathway in response to DNA damage	1	324.1×	0.005	PIK3R1
cellular response to UV	1	295.6×	0.005	PIK3R1
positive regulation of protein localization to plasma membrane	1	271.8×	0.006	PIK3R1
insulin receptor signaling pathway	1	221.7×	0.006	PIK3R1
B cell differentiation	1	218.9×	0.006	PIK3R1

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
PIK3R1	IDELALISIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIK3R1	26	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IDELALISIB	4	PIK3R1
ALPELISIB	4	PIK3R1
DUVELISIB	4	PIK3R1
COPANLISIB	4	PIK3R1
UMBRALISIB	4	PIK3R1
DACTOLISIB	3	PIK3R1
BUPARLISIB	3	PIK3R1
QUERCETIN	3	PIK3R1
OMIPALISIB	2	PIK3R1
VISTUSERTIB	2	PIK3R1
FIMEPINOSTAT	2	PIK3R1
EGANELISIB	2	PIK3R1
BERZOSERTIB	2	PIK3R1
BIMIRALISIB	2	PIK3R1
PICTILISIB	2	PIK3R1
ZSTK-474	2	PIK3R1
GSK-2636771	2	PIK3R1
AMDIZALISIB	2	PIK3R1
RISOVALISIB	2	PIK3R1
DEZAPELISIB	2	PIK3R1
ROGINOLISIB	2	PIK3R1
AZD-8055	1	PIK3R1
VS-5584	1	PIK3R1
AZD-8186	1	PIK3R1
GS-9901	1	PIK3R1
AZD-7648	1	PIK3R1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PIK3R1	493	Binding:470, ADMET:23

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
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
PIK3R1	493

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

26 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	PIK3R1
ALPELISIB	4	PIK3R1
DUVELISIB	4	PIK3R1
COPANLISIB	4	PIK3R1
UMBRALISIB	4	PIK3R1
DACTOLISIB	3	PIK3R1
BUPARLISIB	3	PIK3R1
QUERCETIN	3	PIK3R1
OMIPALISIB	2	PIK3R1
VISTUSERTIB	2	PIK3R1
FIMEPINOSTAT	2	PIK3R1
EGANELISIB	2	PIK3R1
BERZOSERTIB	2	PIK3R1
BIMIRALISIB	2	PIK3R1
PICTILISIB	2	PIK3R1
ZSTK-474	2	PIK3R1
GSK-2636771	2	PIK3R1
AMDIZALISIB	2	PIK3R1
RISOVALISIB	2	PIK3R1
DEZAPELISIB	2	PIK3R1
ROGINOLISIB	2	PIK3R1
AZD-8055	1	PIK3R1
VS-5584	1	PIK3R1
AZD-8186	1	PIK3R1
GS-9901	1	PIK3R1
AZD-7648	1	PIK3R1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	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	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.