Agammaglobulinemia 4, autosomal recessive

Summary

Agammaglobulinemia 4, autosomal recessive (MONDO:0013289) is a disease caused by BLNK (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: BLNK (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 340

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	agammaglobulinemia 4, autosomal recessive
Mondo ID	MONDO:0013289
OMIM	613502
DOID	DOID:0060027
UMLS	C3150752
MedGen	462102
GARD	0015674
Is cancer (heuristic)	no

Also known as: agammaglobulinemia 4, autosomal recessive · agammaglobulinemia, autosomal recessive, due to Blnk defect · AGM4 · autosomal agammaglobulinemia caused by mutation in BLNK · B cell linker protein deficiency · BLNK autosomal agammaglobulinemia

Data availability: 340 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 4, autosomal recessive

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

340 retrieved; paginated sample, class counts are floors:

175 likely benign, 125 uncertain significance, 17 benign, 9 pathogenic, 6 likely pathogenic, 5 conflicting classifications of pathogenicity, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1072783	NM_013314.4(BLNK):c.1195C>T (p.Arg399Ter)	BLNK	Pathogenic	criteria provided, single submitter
1075117	NM_013314.4(BLNK):c.1031del (p.Lys344fs)	BLNK	Pathogenic	criteria provided, single submitter
2090455	NM_013314.4(BLNK):c.26del (p.Val9fs)	BLNK	Pathogenic	criteria provided, single submitter
3661859	NM_013314.4(BLNK):c.252C>A (p.Tyr84Ter)	BLNK	Pathogenic	criteria provided, single submitter
3729465	NC_000010.11:g.96201059del	BLNK	Pathogenic	criteria provided, single submitter
4845848	NM_013314.4(BLNK):c.676+1G>A	BLNK	Pathogenic	criteria provided, single submitter
538835	NC_000010.11:g.96242785del	BLNK	Pathogenic	criteria provided, single submitter
5507	NM_013314.4(BLNK):c.47+3A>T	BLNK	Pathogenic	no assertion criteria provided
831064	NC_000010.11:g.(?96271332)(96271418_?)del	BLNK	Pathogenic	criteria provided, single submitter
1348172	NM_013314.4(BLNK):c.113+2T>G	BLNK	Likely pathogenic	criteria provided, single submitter
2860444	NM_013314.4(BLNK):c.747-2A>G	BLNK	Likely pathogenic	criteria provided, single submitter
3065608	NM_013314.4(BLNK):c.145C>T (p.Arg49Ter)	BLNK	Likely pathogenic	criteria provided, single submitter
3768783	NM_013314.4(BLNK):c.902+2T>C	BLNK	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4075317	NM_013314.4(BLNK):c.289G>T (p.Glu97Ter)	BLNK	Likely pathogenic	criteria provided, single submitter
976234	NM_013314.4(BLNK):c.746+1G>A	BLNK	Likely pathogenic	criteria provided, single submitter
1031777	NM_013314.4(BLNK):c.205-15C>T	BLNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2201098	NM_013314.4(BLNK):c.719C>T (p.Ala240Val)	BLNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
402428	NM_013314.4(BLNK):c.115C>T (p.Leu39=)	BLNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
444234	NM_013314.4(BLNK):c.923T>C (p.Ile308Thr)	BLNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
568111	NM_013314.4(BLNK):c.1021G>A (p.Val341Ile)	BLNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1062671	NC_000010.10:g.(?97366499)(98031175_?)dup	ALDH18A1	Uncertain significance	criteria provided, single submitter
1000383	NM_013314.4(BLNK):c.273C>A (p.Asn91Lys)	BLNK	Uncertain significance	criteria provided, multiple submitters, no conflicts
1011373	NM_013314.4(BLNK):c.284G>A (p.Ser95Asn)	BLNK	Uncertain significance	criteria provided, single submitter
1013812	NM_013314.4(BLNK):c.646A>G (p.Thr216Ala)	BLNK	Uncertain significance	criteria provided, multiple submitters, no conflicts
1016106	NM_013314.4(BLNK):c.328C>G (p.Pro110Ala)	BLNK	Uncertain significance	criteria provided, single submitter
1022366	NM_013314.4(BLNK):c.434A>G (p.Glu145Gly)	BLNK	Uncertain significance	criteria provided, single submitter
1024554	NM_013314.4(BLNK):c.377A>G (p.Gln126Arg)	BLNK	Uncertain significance	criteria provided, single submitter
1026824	NM_013314.4(BLNK):c.201C>G (p.Asp67Glu)	BLNK	Uncertain significance	criteria provided, single submitter
1043293	NM_013314.4(BLNK):c.509G>A (p.Gly170Asp)	BLNK	Uncertain significance	criteria provided, single submitter
1044681	NM_013314.4(BLNK):c.970C>T (p.Pro324Ser)	BLNK	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 6 · 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
BLNK	Strong	Autosomal recessive	agammaglobulinemia 4, autosomal recessive	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BLNK	Orphanet:33110	Autosomal non-syndromic agammaglobulinemia
ALDH18A1	Orphanet:35664	ALDH18A1-related De Barsy syndrome
ALDH18A1	Orphanet:447753	Autosomal dominant spastic paraplegia type 9A
ALDH18A1	Orphanet:447757	Autosomal dominant spastic paraplegia type 9B
ALDH18A1	Orphanet:447760	Autosomal recessive spastic paraplegia type 9B
ALDH18A1	Orphanet:90348	Autosomal dominant cutis laxa

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BLNK	HGNC:14211	ENSG00000095585	Q8WV28	B-cell linker protein	gencc,clinvar
ZNF518A	HGNC:29009	ENSG00000177853	Q6AHZ1	Zinc finger protein 518A	clinvar
ALDH18A1	HGNC:9722	ENSG00000059573	P54886	Delta-1-pyrroline-5-carboxylate synthase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BLNK	B-cell linker protein	Functions as a central linker protein, downstream of the B-cell receptor (BCR), bridging the SYK kinase to a multitude of signaling pathways and regulating biological outcomes of B-cell function and development.
ZNF518A	Zinc finger protein 518A	Through its association with the EHMT1-EHMT2/G9A and PRC2/EED-EZH2 histone methyltransferase complexes may function in gene silencing, regulating repressive post-translational methylation of histone tails at promoters of target genes.
ALDH18A1	Delta-1-pyrroline-5-carboxylate synthase	Bifunctional enzyme that converts glutamate to glutamate 5-semialdehyde, an intermediate in the biosynthesis of proline, ornithine and arginine.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 0 · Druggable fraction: 0.33

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	9.2×	0.246
Scaffold/PPI	1	5.8×	0.246
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BLNK	Scaffold/PPI	no		SH2, SH2_dom_sf, Immunoreceptor_sig_adapters
ZNF518A	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, ZnF_C2H2-type_TF
ALDH18A1	Kinase	yes		GPR_dom, Asp/Glu/Uridylate_kinase, Glu/AcGlu_kinase

Expression context

Cohort genes with no expression data: 0.

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	0

Top tissues across cohort

Tissue	Cohort genes
corpus epididymis	1
oral cavity	1
tongue squamous epithelium	1
adrenal tissue	1
buccal mucosa cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
ileal mucosa	1
jejunal mucosa	1
parotid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BLNK	257	broad	marker	tongue squamous epithelium, oral cavity, corpus epididymis
ZNF518A	280	ubiquitous	marker	buccal mucosa cell, male germ line stem cell (sensu Vertebrata) in testis, adrenal tissue
ALDH18A1	263	ubiquitous	marker	parotid gland, jejunal mucosa, ileal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALDH18A1	7,351
BLNK	1,475
ZNF518A	920

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BLNK	Q8WV28	1
ALDH18A1	P54886	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ZNF518A	Q6AHZ1	40.97

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 3 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
Glutamate and glutamine metabolism	1	407.9×	0.019	ALDH18A1
Regulation of signaling by CBL	1	248.3×	0.019	BLNK
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	1	178.4×	0.019	BLNK
Signaling by the B Cell Receptor (BCR)	1	173.0×	0.019	BLNK
Interleukin-3, Interleukin-5 and GM-CSF signaling	1	158.6×	0.019	BLNK
Potential therapeutics for SARS	1	57.1×	0.037	BLNK
Mitochondrial protein degradation	1	57.1×	0.037	ALDH18A1
Signaling by Interleukins	1	32.1×	0.058	BLNK
SARS-CoV Infections	1	27.7×	0.060	BLNK
Cytokine Signaling in Immune system	1	20.4×	0.073	BLNK
Viral Infection Pathways	1	15.4×	0.082	BLNK
Adaptive Immune System	1	14.9×	0.082	BLNK
Infectious disease	1	12.4×	0.091	BLNK
Disease	1	6.5×	0.148	BLNK
Immune System	1	6.5×	0.148	BLNK

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
L-ornithine biosynthetic process	1	5617.3×	0.002	ALDH18A1
L-citrulline biosynthetic process	1	1404.3×	0.005	ALDH18A1
L-proline biosynthetic process	1	936.2×	0.005	ALDH18A1
response to temperature stimulus	1	510.7×	0.007	ALDH18A1
glutamate metabolic process	1	374.5×	0.007	ALDH18A1
B cell receptor signaling pathway	1	133.8×	0.017	BLNK
humoral immune response	1	93.6×	0.021	BLNK
B cell differentiation	1	73.0×	0.024	BLNK
cell surface receptor protein tyrosine kinase signaling pathway	1	57.9×	0.027	BLNK
chromatin organization	1	33.0×	0.042	ZNF518A
positive regulation of gene expression	1	12.9×	0.083	BLNK
intracellular signal transduction	1	12.7×	0.083	BLNK
inflammatory response	1	12.6×	0.083	BLNK
regulation of transcription by RNA polymerase II	1	3.9×	0.236	ZNF518A

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BLNK	0	0
ZNF518A	0	0
ALDH18A1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ALDH18A1	3	Binding:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ALDH18A1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	BLNK, ZNF518A

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)
BLNK	0	—
ZNF518A	0	—
ALDH18A1	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.