Autosomal recessive agammaglobulinemia 1

Summary

Autosomal recessive agammaglobulinemia 1 (MONDO:0020729) is a disease caused by IGHM (GenCC Definitive), with 4 cohort genes. The dominant Reactome pathway is Antigen activates B Cell Receptor (BCR) leading to generation of second messengers (3 cohort genes).

At a glance

• Causal gene: IGHM (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 32

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive agammaglobulinemia 1
Mondo ID	MONDO:0020729
OMIM	601495
DOID	DOID:0081136
UMLS	C3152144
MedGen	463494
GARD	0025227
Is cancer (heuristic)	no

Also known as: agammaglobulinemia 1, autosomal recessive · AGM1 · autosomal recessive agammaglobulinemia 1

Data availability: 32 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 › autosomal recessive agammaglobulinemia 1

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

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

32 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
11342	NM_000061.3(BTK):c.1574G>A (p.Arg525Gln)	BTK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11348	NM_000061.3(BTK):c.83G>A (p.Arg28His)	BTK	Pathogenic	criteria provided, multiple submitters, no conflicts
11363	NM_000061.3(BTK):c.763C>T (p.Arg255Ter)	BTK	Pathogenic	criteria provided, multiple submitters, no conflicts
11377	NM_000061.3(BTK):c.1558C>T (p.Arg520Ter)	BTK	Pathogenic	criteria provided, multiple submitters, no conflicts
11383	NM_000061.3(BTK):c.1684C>T (p.Arg562Trp)	BTK	Pathogenic	criteria provided, multiple submitters, no conflicts
492809	NM_000061.3(BTK):c.141+3_141+6del	BTK	Pathogenic	no assertion criteria provided
492810	NM_000061.3(BTK):c.161del (p.Gly54fs)	BTK	Pathogenic	no assertion criteria provided
492811	NM_000061.3(BTK):c.371G>A (p.Trp124Ter)	BTK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
492812	NM_000061.3(BTK):c.435C>A (p.Cys145Ter)	BTK	Pathogenic	no assertion criteria provided
492813	NM_000061.3(BTK):c.863G>A (p.Arg288Gln)	BTK	Pathogenic	criteria provided, multiple submitters, no conflicts
492814	NM_000061.3(BTK):c.953C>T (p.Ser318Phe)	BTK	Pathogenic	no assertion criteria provided
492815	NM_000061.3(BTK):c.1116G>C (p.Arg372Ser)	BTK	Pathogenic	no assertion criteria provided
492817	NM_000061.3(BTK):c.1567-2A>T	BTK	Pathogenic	no assertion criteria provided
492818	NM_000061.3(BTK):c.1581_1584del (p.Cys527fs)	BTK	Pathogenic	criteria provided, multiple submitters, no conflicts
492819	NM_000061.3(BTK):c.1630_1631+3delinsGAAA	BTK	Pathogenic	no assertion criteria provided
492820	NM_000061.3(BTK):c.1706T>C (p.Leu569Pro)	BTK	Pathogenic	no assertion criteria provided
492821	NM_000061.3(BTK):c.1946del (p.Ser649fs)	BTK	Pathogenic	no assertion criteria provided
14810	NC_000014.9:g.105854405C>T	IGH	Pathogenic	no assertion criteria provided
14812	NC_000014.9:g.105855623_105855624del	IGH	Pathogenic	no assertion criteria provided
14813	NC_000014.9:g.105855107C>T	IGH	Pathogenic	no assertion criteria provided
156278	NC_000014.9:g.105854468A>C	IGH	Pathogenic	no assertion criteria provided
427234	NC_000014.9:g.105856087G>A	IGH	Pathogenic	no assertion criteria provided
14809	IGHM, 75-KB DEL	IGHM	Pathogenic	no assertion criteria provided
1339539	NC_000014.9:g.105856013G>T	IGH	Likely pathogenic	criteria provided, single submitter
973583	NC_000014.9:g.105855132dup	IGH	Likely pathogenic	criteria provided, single submitter
492816	NM_000061.3(BTK):c.1475G>A (p.Arg492His)	BTK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
587546	NM_001783.4(CD79A):c.419C>T (p.Thr140Ile)	CD79A	Uncertain significance	criteria provided, multiple submitters, no conflicts
2428589	NC_000014.9:g.105855203G>A	IGH	Benign	criteria provided, single submitter
439814	NC_000014.9:g.105855988G>C	IGH	Benign	criteria provided, single submitter
439815	NC_000014.9:g.105856156C>T	IGH	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 8 · 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
IGHM	Definitive	Autosomal recessive	autosomal recessive agammaglobulinemia 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IGHM	Orphanet:33110	Autosomal non-syndromic agammaglobulinemia
BTK	Orphanet:47	X-linked agammaglobulinemia
BTK	Orphanet:632	Short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia
CD79A	Orphanet:33110	Autosomal non-syndromic agammaglobulinemia
IGH	Orphanet:52416	Mantle cell lymphoma
IGH	Orphanet:52417	MALT lymphoma
IGH	Orphanet:545	Follicular lymphoma
IGH	Orphanet:585948	B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3)

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IGHM	HGNC:5541	ENSG00000211899	P01871	Immunoglobulin heavy constant mu	gencc,clinvar
BTK	HGNC:1133	ENSG00000010671	Q06187	Tyrosine-protein kinase BTK	clinvar
CD79A	HGNC:1698	ENSG00000105369	P11912	B-cell antigen receptor complex-associated protein alpha chain	clinvar
IGH	HGNC:5477			immunoglobulin heavy locus	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IGHM	Immunoglobulin heavy constant mu	Constant region of immunoglobulin heavy chains.
BTK	Tyrosine-protein kinase BTK	Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling.
CD79A	B-cell antigen receptor complex-associated protein alpha chain	Required in cooperation with CD79B for initiation of the signal transduction cascade activated by binding of antigen to the B-cell antigen receptor complex (BCR) which leads to internalization of the complex, trafficking to late endosomes…

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
Antibody/Immunoglobulin	2	14.6×	0.020
Kinase	1	6.9×	0.205
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IGHM	Antibody/Immunoglobulin	yes		Ig/MHC_CS, Ig_C1-set, Ig-like_dom
BTK	Kinase	yes	2.7.10.2	Prot_kinase_dom, SH2, Ser-Thr/Tyr_kinase_cat_dom
CD79A	Antibody/Immunoglobulin	yes		Phos_immunorcpt_sig_ITAM, Ig_sub2, Ig_sub
IGH	Other/Unknown	no

Expression context

Cohort genes with no expression data: 1.

3 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)	3
unknown	1

Top tissues across cohort

Tissue	Cohort genes
granulocyte	2
spleen	2
vermiform appendix	1
leukocyte	1
monocyte	1
mononuclear cell	1
lymph node	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IGHM	180	tissue_specific	marker	spleen, granulocyte, vermiform appendix
BTK	206	broad	marker	monocyte, mononuclear cell, leukocyte
CD79A	182	broad	marker	spleen, granulocyte, lymph node
IGH

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BTK	4,467
CD79A	3,177
IGHM	93
IGH	0

Intra-cohort edges

A	B	Sources
BTK	CD79A	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BTK	Q06187	156
IGHM	P01871	31
CD79A	P11912	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 47. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	3	356.9×	9e-07	IGHM, BTK, CD79A
CD22 mediated BCR regulation	2	1522.7×	1e-05	IGHM, CD79A
Potential therapeutics for SARS	3	114.2×	1e-05	IGHM, BTK, CD79A
Signaling by the B Cell Receptor (BCR)	2	230.7×	3e-04	BTK, CD79A
SARS-CoV Infections	2	37.0×	0.009	BTK, CD79A
G-protein beta:gamma signalling	1	634.4×	0.012	BTK
Diseases of Immune System	1	292.8×	0.016	BTK
Diseases associated with the TLR signaling cascade	1	292.8×	0.016	BTK
Viral Infection Pathways	2	20.5×	0.016	BTK, CD79A
Adaptive Immune System	2	19.9×	0.016	BTK, CD79A
G beta:gamma signalling through BTK	1	211.5×	0.018	BTK
MyD88 deficiency (TLR2/4)	1	200.3×	0.018	BTK
IRAK4 deficiency (TLR2/4)	1	190.3×	0.018	BTK
Infectious disease	2	16.6×	0.018	BTK, CD79A
DAP12 interactions	1	158.6×	0.020	BTK
DAP12 signaling	1	122.8×	0.021	BTK
FCERI mediated Ca+2 mobilization	1	119.0×	0.021	BTK
Parasite infection	1	115.3×	0.021	BTK
Leishmania phagocytosis	1	115.3×	0.021	BTK
Antigen processing-Cross presentation	1	105.7×	0.021	BTK
RHO GTPases Activate WASPs and WAVEs	1	105.7×	0.021	BTK
Fcgamma receptor (FCGR) dependent phagocytosis	1	92.8×	0.022	BTK
Fc epsilon receptor (FCERI) signaling	1	90.6×	0.022	BTK
FCGR3A-mediated phagocytosis	1	62.4×	0.027	BTK
Regulation of actin dynamics for phagocytic cup formation	1	61.4×	0.027	BTK
Toll Like Receptor TLR6:TLR2 Cascade	1	58.6×	0.027	BTK
Toll Like Receptor 2 (TLR2) Cascade	1	57.7×	0.027	BTK
Toll Like Receptor TLR1:TLR2 Cascade	1	56.0×	0.027	BTK
Leishmania infection	1	54.4×	0.027	BTK
Parasitic Infection Pathways	1	54.4×	0.027	BTK

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
B cell receptor signaling pathway	3	401.2×	7e-07	IGHM, BTK, CD79A
adaptive immune response	3	84.3×	4e-05	IGHM, BTK, CD79A
B cell activation	2	303.6×	2e-04	BTK, CD79A
regulation of B cell cytokine production	1	5617.3×	0.001	BTK
monocyte proliferation	1	5617.3×	0.001	BTK
positive regulation of interleukin-17A production	1	5617.3×	0.001	BTK
positive regulation of type I hypersensitivity	1	2808.7×	0.002	BTK
B cell affinity maturation	1	2808.7×	0.002	BTK
regulation of B cell apoptotic process	1	2808.7×	0.002	BTK
positive regulation of type III hypersensitivity	1	1872.4×	0.002	BTK
pre-B cell allelic exclusion	1	1872.4×	0.002	IGHM
proteoglycan catabolic process	1	1872.4×	0.002	BTK
positive regulation of synoviocyte proliferation	1	1872.4×	0.002	BTK
eosinophil homeostasis	1	1872.4×	0.002	BTK
cellular response to molecule of fungal origin	1	1404.3×	0.002	BTK
histamine secretion by mast cell	1	1123.5×	0.003	BTK
positive regulation of cGAS/STING signaling pathway	1	702.2×	0.004	BTK
neutrophil homeostasis	1	510.7×	0.005	BTK
cellular response to interleukin-7	1	432.1×	0.006	BTK
positive regulation of B cell differentiation	1	374.5×	0.006	BTK
innate immune response	2	22.4×	0.006	IGHM, BTK
MyD88-dependent toll-like receptor signaling pathway	1	312.1×	0.006	BTK
negative regulation of B cell proliferation	1	312.1×	0.006	BTK
negative regulation of interleukin-10 production	1	244.2×	0.008	BTK
Fc-epsilon receptor signaling pathway	1	244.2×	0.008	BTK
positive regulation of NLRP3 inflammasome complex assembly	1	193.7×	0.009	BTK
mesoderm development	1	175.5×	0.010	BTK
positive regulation of immunoglobulin production	1	160.5×	0.010	BTK
B cell proliferation	1	160.5×	0.010	CD79A
cell maturation	1	147.8×	0.010	BTK

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) 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
BTK	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BTK	84	4
IGHM	0	0
CD79A	0	0
IGH	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	BTK
FEDRATINIB	4	BTK
NERATINIB	4	BTK
IBRUTINIB	4	BTK
ENTRECTINIB	4	BTK
CERITINIB	4	BTK
VANDETANIB	4	BTK
BOSUTINIB	4	BTK
OSIMERTINIB	4	BTK
BRIGATINIB	4	BTK
FUTIBATINIB	4	BTK
ACALABRUTINIB	4	BTK
OLMUTINIB	4	BTK
ZANUBRUTINIB	4	BTK
TIRABRUTINIB	4	BTK
RITLECITINIB	4	BTK
PIRTOBRUTINIB	4	BTK
NINTEDANIB	4	BTK
SUNITINIB	4	BTK
DASATINIB	4	BTK
MITOXANTRONE	4	BTK
CRIZOTINIB	4	BTK
SARACATINIB	3	BTK
CANERTINIB	3	BTK
ENTOSPLETINIB	3	BTK
TESEVATINIB	3	BTK
POZIOTINIB	3	BTK
ROCILETINIB	3	BTK
PYROTINIB	3	BTK
RILZABRUTINIB	3	BTK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
BTK	1,836	Binding:1810, Functional:23, ADMET:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BTK	2.7.10.2	non-specific protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
BTK	1,836

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)
PONATINIB	4	BTK
FEDRATINIB	4	BTK
NERATINIB	4	BTK
IBRUTINIB	4	BTK
ENTRECTINIB	4	BTK
CERITINIB	4	BTK
VANDETANIB	4	BTK
BOSUTINIB	4	BTK
OSIMERTINIB	4	BTK
BRIGATINIB	4	BTK
FUTIBATINIB	4	BTK
ACALABRUTINIB	4	BTK
OLMUTINIB	4	BTK
ZANUBRUTINIB	4	BTK
TIRABRUTINIB	4	BTK
RITLECITINIB	4	BTK
PIRTOBRUTINIB	4	BTK
NINTEDANIB	4	BTK
SUNITINIB	4	BTK
DASATINIB	4	BTK
MITOXANTRONE	4	BTK
CRIZOTINIB	4	BTK
SARACATINIB	3	BTK
CANERTINIB	3	BTK
ENTOSPLETINIB	3	BTK
TESEVATINIB	3	BTK
POZIOTINIB	3	BTK
ROCILETINIB	3	BTK
PYROTINIB	3	BTK
RILZABRUTINIB	3	BTK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	BTK
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	IGHM, CD79A
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	IGH

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
IGHM	0	—
CD79A	0	—
IGH	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.