Agammaglobulinemia 5, autosomal dominant

Summary

Agammaglobulinemia 5, autosomal dominant (MONDO:0013290) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 20

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	agammaglobulinemia 5, autosomal dominant
Mondo ID	MONDO:0013290
OMIM	613506
DOID	DOID:0080588
UMLS	C3150753
MedGen	462103
GARD	0015675
Is cancer (heuristic)	no

Also known as: agammaglobulinemia 5, autosomal dominant · AGM5 · autosomal agammaglobulinemia caused by mutation in LRRC8A · LRRC8A autosomal agammaglobulinemia

Data availability: 20 ClinVar variants · 1 GenCC gene-disease record.

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 5, autosomal dominant

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

20 retrieved; paginated sample, class counts are floors:

11 benign, 3 likely benign, 2 benign/likely benign, 2 conflicting classifications of pathogenicity, 1 uncertain significance, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2374	NC_000009.12:g.12891379_qterdelins[T;NC_000020.11:g.47204889_qterinv]		Pathogenic	no assertion criteria provided
801365	NM_019594.4(LRRC8A):c.203C>T (p.Ser68Leu)	LRRC8A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
801366	NM_019594.4(LRRC8A):c.1586C>T (p.Ala529Val)	LRRC8A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028633	NM_019594.4(LRRC8A):c.2267del (p.Leu756fs)	LRRC8A	Uncertain significance	criteria provided, single submitter
1168526	NM_019594.4(LRRC8A):c.2157+11C>T	LRRC8A	Benign	criteria provided, multiple submitters, no conflicts
1635972	NM_019594.4(LRRC8A):c.33G>A (p.Ala11=)	LRRC8A	Likely benign	criteria provided, multiple submitters, no conflicts
2920758	NM_019594.4(LRRC8A):c.-2C>T	LRRC8A	Benign	criteria provided, single submitter
403060	NM_019594.4(LRRC8A):c.1014T>C (p.Tyr338=)	LRRC8A	Benign	criteria provided, multiple submitters, no conflicts
403061	NM_019594.4(LRRC8A):c.1476T>C (p.Arg492=)	LRRC8A	Benign	criteria provided, multiple submitters, no conflicts
439872	NM_019594.4(LRRC8A):c.1699G>A (p.Val567Met)	LRRC8A	Likely benign	criteria provided, multiple submitters, no conflicts
439873	NM_019594.4(LRRC8A):c.1509C>T (p.Thr503=)	LRRC8A	Benign	criteria provided, multiple submitters, no conflicts
439874	NM_019594.4(LRRC8A):c.774C>T (p.Asp258=)	LRRC8A	Benign	criteria provided, multiple submitters, no conflicts
4819243	NM_019594.4(LRRC8A):c.580A>T (p.Met194Leu)	LRRC8A	Likely benign	criteria provided, single submitter
618709	NM_019594.4(LRRC8A):c.1371C>T (p.Pro457=)	LRRC8A	Benign	criteria provided, multiple submitters, no conflicts
716394	NM_019594.4(LRRC8A):c.51C>T (p.Tyr17=)	LRRC8A	Benign	criteria provided, multiple submitters, no conflicts
722489	NM_019594.4(LRRC8A):c.1606G>A (p.Val536Ile)	LRRC8A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
776451	NM_019594.4(LRRC8A):c.1458C>T (p.Pro486=)	LRRC8A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
776452	NM_019594.4(LRRC8A):c.1803T>C (p.Cys601=)	LRRC8A	Benign	criteria provided, multiple submitters, no conflicts
776453	NM_019594.4(LRRC8A):c.1995G>A (p.Glu665=)	LRRC8A	Benign	criteria provided, multiple submitters, no conflicts
810955	NM_019594.4(LRRC8A):c.2118C>G (p.Leu706=)	LRRC8A	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 1 · 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
LRRC8A	Supportive	Autosomal dominant	autosomal agammaglobulinemia	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LRRC8A	Orphanet:33110	Autosomal non-syndromic agammaglobulinemia

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
LRRC8A	HGNC:19027	ENSG00000136802	Q8IWT6	Volume-regulated anion channel subunit LRRC8A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LRRC8A	Volume-regulated anion channel subunit LRRC8A	Essential component of the volume-regulated anion channel (VRAC, also named VSOAC channel), an anion channel required to maintain a constant cell volume in response to extracellular or intracellular osmotic changes.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LRRC8A	Other/Unknown	no		Leu-rich_rpt, Leu-rich_rpt_typical-subtyp, LRRC8_Pannexin-like

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
gingiva	1
gingival epithelium	1
nasal cavity epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LRRC8A	262	ubiquitous	marker	gingival epithelium, nasal cavity epithelium, gingiva

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LRRC8A	1,554

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LRRC8A	Q8IWT6	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Miscellaneous transport and binding events	1	439.2×	0.005	LRRC8A
Transport of small molecules	1	25.1×	0.040	LRRC8A

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
pre-B cell differentiation	1	16852.0×	8e-04	LRRC8A
taurine transmembrane transport	1	2808.7×	0.001	LRRC8A
monoatomic anion transmembrane transport	1	2808.7×	0.001	LRRC8A
cyclic-GMP-AMP transmembrane import across plasma membrane	1	2106.5×	0.001	LRRC8A
response to osmotic stress	1	1532.0×	0.001	LRRC8A
monoatomic anion transport	1	1404.3×	0.001	LRRC8A
aspartate transmembrane transport	1	1404.3×	0.001	LRRC8A
protein hexamerization	1	1404.3×	0.001	LRRC8A
cell volume homeostasis	1	601.9×	0.002	LRRC8A
intracellular glucose homeostasis	1	581.1×	0.002	LRRC8A
positive regulation of myoblast differentiation	1	366.4×	0.003	LRRC8A
positive regulation of insulin secretion	1	255.3×	0.005	LRRC8A
chloride transmembrane transport	1	237.3×	0.005	LRRC8A
spermatogenesis	1	35.2×	0.028	LRRC8A

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LRRC8A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	LRRC8A

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)
LRRC8A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.