Agammaglobulinemia 7, autosomal recessive

Summary

Agammaglobulinemia 7, autosomal recessive (MONDO:0014083) is a disease caused by PIK3R1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: PIK3R1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 533

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	agammaglobulinemia 7, autosomal recessive
Mondo ID	MONDO:0014083
OMIM	615214
DOID	DOID:0081139
UMLS	C3554689
MedGen	767603
GARD	0015918
Is cancer (heuristic)	no

Also known as: agammaglobulinemia 7, autosomal recessive · AGM7 · autosomal agammaglobulinemia caused by mutation in PIK3R1 · PIK3R1 autosomal agammaglobulinemia

Data availability: 533 ClinVar variants · 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 › isolated agammaglobulinemia › autosomal agammaglobulinemia › agammaglobulinemia 7, autosomal recessive

Related subtypes (7): agammaglobulinemia 6, autosomal recessive, agammaglobulinemia 2, autosomal recessive, agammaglobulinemia 3, autosomal recessive, agammaglobulinemia 4, autosomal recessive, agammaglobulinemia 5, autosomal dominant, agammaglobulinemia 8, autosomal dominant, autosomal recessive agammaglobulinemia 1

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

533 retrieved; paginated sample, class counts are floors:

250 uncertain significance, 215 likely benign, 22 pathogenic, 14 conflicting classifications of pathogenicity, 14 benign/likely benign, 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
3901222	NM_181523.3(PIK3R1):c.703C>T (p.Gln235Ter)	PIK3R1	Pathogenic	criteria provided, single submitter
3906270	NM_181523.3(PIK3R1):c.244dup (p.Ile82fs)	PIK3R1	Pathogenic	no assertion criteria provided
446497	NM_181523.3(PIK3R1):c.1425+2T>A	PIK3R1	Pathogenic	criteria provided, multiple submitters, no conflicts
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
998150	NM_181523.3(PIK3R1):c.1344del (p.Lys448fs)	PIK3R1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1524499	NM_181523.3(PIK3R1):c.1300-5_1320del	PIK3R1	Likely pathogenic	criteria provided, single submitter
2029429	NM_181523.3(PIK3R1):c.916+2T>C	PIK3R1	Likely pathogenic	criteria provided, single submitter
2061060	NM_181523.3(PIK3R1):c.1946G>A (p.Arg649Gln)	PIK3R1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 4 · 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	Strong	Autosomal recessive	agammaglobulinemia 7, autosomal recessive	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
ANGPT1	Orphanet:599418	Hereditary angioedema with normal C1Inh not related to F12 or PLG variant

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PIK3R1	HGNC:8979	ENSG00000145675	P27986	Phosphatidylinositol 3-kinase regulatory subunit alpha	gencc,clinvar
ANGPT1	HGNC:484	ENSG00000154188	Q15389	Angiopoietin-1	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.
ANGPT1	Angiopoietin-1	Binds and activates TEK/TIE2 receptor by inducing its dimerization and tyrosine phosphorylation.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PIK3R1	Kinase	yes	2.7.1.153	RhoGAP_dom, SH2, SH3_domain
ANGPT1	Other/Unknown	no		Fibrinogen_a/b/g_C_dom, Fibrinogen_a/b/g_C_1, Fibrinogen_CS

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	2
caput epididymis	1
corpus epididymis	1
cranial nerve II	1
lower lobe of lung	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
ANGPT1	250	ubiquitous	marker	lower lobe of lung, calcaneal tendon, cranial nerve II

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PIK3R1	5,168
ANGPT1	2,194

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PIK3R1	P27986	105
ANGPT1	Q15389	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 83. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Tie2 Signaling	2	601.0×	2e-04	PIK3R1, ANGPT1
MET activates PI3K/AKT signaling	1	951.7×	0.010	PIK3R1
Activated NTRK3 signals through PI3K	1	951.7×	0.010	PIK3R1
Activated NTRK2 signals through PI3K	1	815.7×	0.010	PIK3R1
Signaling by LTK in cancer	1	815.7×	0.010	PIK3R1
PI3K/AKT activation	1	634.4×	0.010	PIK3R1
IRS-mediated signalling	1	519.1×	0.010	PIK3R1
PI3K events in ERBB4 signaling	1	519.1×	0.010	PIK3R1
Co-stimulation by ICOS	1	519.1×	0.010	PIK3R1
GP1b-IX-V activation signalling	1	475.8×	0.010	PIK3R1
Signaling by FGFR4 in disease	1	475.8×	0.010	PIK3R1
Erythropoietin activates Phosphoinositide-3-kinase (PI3K)	1	475.8×	0.010	PIK3R1
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	1	439.2×	0.010	PIK3R1
Signaling by PDGFRA extracellular domain mutants	1	439.2×	0.010	PIK3R1
Signaling by LTK	1	439.2×	0.010	PIK3R1
Signaling by FLT3 ITD and TKD mutants	1	380.7×	0.010	PIK3R1
Constitutive Signaling by EGFRvIII	1	356.9×	0.010	PIK3R1
PI3K events in ERBB2 signaling	1	335.9×	0.010	PIK3R1
Signaling by ERBB2 ECD mutants	1	335.9×	0.010	PIK3R1
GAB1 signalosome	1	317.2×	0.010	PIK3R1
Signaling by cytosolic FGFR1 fusion mutants	1	317.2×	0.010	PIK3R1
PI-3K cascade:FGFR3	1	317.2×	0.010	PIK3R1
Role of LAT2/NTAL/LAB on calcium mobilization	1	300.5×	0.010	PIK3R1
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	1	285.5×	0.010	PIK3R1
Signaling by ALK	1	285.5×	0.010	PIK3R1
PI-3K cascade:FGFR4	1	285.5×	0.010	PIK3R1
Signaling by FLT3 fusion proteins	1	285.5×	0.010	PIK3R1
PI-3K cascade:FGFR1	1	259.6×	0.010	PIK3R1
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	1	259.6×	0.010	PIK3R1
PI-3K cascade:FGFR2	1	248.3×	0.010	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 2 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 macrophage migration inhibitory factor signaling pathway	1	8426.0×	0.005	ANGPT1
activation of transmembrane receptor protein tyrosine kinase activity	1	2808.7×	0.005	ANGPT1
regulation of toll-like receptor 4 signaling pathway	1	2808.7×	0.005	PIK3R1
positive regulation of endoplasmic reticulum unfolded protein response	1	2808.7×	0.005	PIK3R1
glomerulus vasculature development	1	2106.5×	0.005	ANGPT1
myeloid leukocyte migration	1	2106.5×	0.005	PIK3R1
Tie signaling pathway	1	1685.2×	0.005	ANGPT1
positive regulation of blood-brain barrier permeability	1	1685.2×	0.005	ANGPT1
negative regulation of cytokine production involved in immune response	1	1404.3×	0.005	ANGPT1
regulation of skeletal muscle satellite cell proliferation	1	1404.3×	0.005	ANGPT1
interleukin-18-mediated signaling pathway	1	1404.3×	0.005	PIK3R1
positive regulation of coagulation	1	1404.3×	0.005	ANGPT1
negative regulation of apoptotic process	2	34.8×	0.005	PIK3R1, ANGPT1
positive regulation of focal adhesion disassembly	1	936.2×	0.006	PIK3R1
heparin proteoglycan biosynthetic process	1	842.6×	0.006	ANGPT1
regulation of tumor necrosis factor production	1	842.6×	0.006	ANGPT1
T follicular helper cell differentiation	1	702.2×	0.006	PIK3R1
negative regulation of vascular endothelial growth factor signaling pathway	1	648.1×	0.007	ANGPT1
growth hormone receptor signaling pathway	1	601.9×	0.007	PIK3R1
negative regulation of vascular permeability	1	561.7×	0.007	ANGPT1
positive regulation of RNA splicing	1	526.6×	0.007	PIK3R1
positive regulation of leukocyte migration	1	495.6×	0.007	PIK3R1
negative regulation of protein import into nucleus	1	468.1×	0.007	ANGPT1
negative regulation of cell-matrix adhesion	1	443.5×	0.007	PIK3R1
positive regulation of peptidyl-tyrosine phosphorylation	1	401.2×	0.007	ANGPT1
positive chemotaxis	1	401.2×	0.007	ANGPT1
cell-substrate adhesion	1	383.0×	0.007	ANGPT1
positive regulation of receptor internalization	1	351.1×	0.008	ANGPT1
positive regulation of lamellipodium assembly	1	300.9×	0.008	PIK3R1
intracellular glucose homeostasis	1	290.6×	0.008	PIK3R1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
ANGPT1	0	0

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
ANGPT1	1	Binding:1

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: 2; 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	1	ANGPT1

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)
ANGPT1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.