Agammaglobulinemia 2, autosomal recessive

Summary

Agammaglobulinemia 2, autosomal recessive (MONDO:0013287) is a disease caused by IGLL1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: IGLL1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 246

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	agammaglobulinemia 2, autosomal recessive
Mondo ID	MONDO:0013287
OMIM	613500
DOID	DOID:0060024, DOID:0081135
UMLS	C3150750
MedGen	462100
GARD	0015672
Is cancer (heuristic)	no

Also known as: agammaglobulinemia 2, autosomal recessive · agammaglobulinemia, autosomal recessive, due to IGLL1 defect · AGM2 · autosomal agammaglobulinemia caused by mutation in IGLL1 · IGLL1 autosomal agammaglobulinemia · lambda 5 deficiency

Data availability: 246 ClinVar variants · 4 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 2, autosomal recessive

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

246 retrieved; paginated sample, class counts are floors:

142 uncertain significance, 74 likely benign, 13 benign/likely benign, 10 benign, 7 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
14825	NM_020070.4(IGLL1):c.425C>T (p.Pro142Leu)	IGLL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
236015	NM_020070.4(IGLL1):c.258del (p.Gln88fs)	IGLL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
439824	NM_020070.4(IGLL1):c.616A>T (p.Thr206Ser)	IGLL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
538828	NM_020070.4(IGLL1):c.334G>A (p.Ala112Thr)	IGLL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
547919	NM_020070.4(IGLL1):c.437C>T (p.Thr146Met)	IGLL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
721827	NM_020070.4(IGLL1):c.67C>T (p.Arg23Cys)	IGLL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
791698	NM_020070.4(IGLL1):c.350C>T (p.Thr117Ile)	IGLL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1442392	NC_000022.10:g.(?23915453)(24237293_?)del	C22orf15	Uncertain significance	criteria provided, single submitter
1002499	NM_020070.4(IGLL1):c.163C>T (p.Pro55Ser)	IGLL1	Uncertain significance	criteria provided, single submitter
1021143	NM_020070.4(IGLL1):c.594C>A (p.His198Gln)	IGLL1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1022099	NM_020070.4(IGLL1):c.322+4A>G	IGLL1	Uncertain significance	criteria provided, single submitter
1025142	NC_000022.10:g.(?23917134)(23922377_?)dup	IGLL1	Uncertain significance	criteria provided, single submitter
1025838	NM_020070.4(IGLL1):c.53C>T (p.Pro18Leu)	IGLL1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1035300	NM_020070.4(IGLL1):c.152_158dup (p.Ala54fs)	IGLL1	Uncertain significance	criteria provided, single submitter
1041092	NC_000022.10:g.(?23922152)(23922397_?)del	IGLL1	Uncertain significance	criteria provided, single submitter
1044631	NM_020070.4(IGLL1):c.606_607del (p.Val203fs)	IGLL1	Uncertain significance	criteria provided, single submitter
1053838	NM_020070.4(IGLL1):c.344C>T (p.Ser115Leu)	IGLL1	Uncertain significance	criteria provided, single submitter
1054982	NM_020070.4(IGLL1):c.550G>A (p.Glu184Lys)	IGLL1	Uncertain significance	criteria provided, single submitter
1057687	NM_020070.4(IGLL1):c.617C>T (p.Thr206Met)	IGLL1	Uncertain significance	criteria provided, single submitter
1063380	NM_020070.4(IGLL1):c.338C>A (p.Thr113Asn)	IGLL1	Uncertain significance	criteria provided, single submitter
1162877	NM_020070.4(IGLL1):c.334_336delinsACT (p.Ala112Thr)	IGLL1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1176009	NM_020070.4(IGLL1):c.454G>A (p.Asp152Asn)	IGLL1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1297738	NM_020070.4(IGLL1):c.157G>T (p.Gly53Ter)	IGLL1	Uncertain significance	criteria provided, single submitter
1345788	NM_020070.4(IGLL1):c.520G>T (p.Ala174Ser)	IGLL1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1346629	NM_020070.4(IGLL1):c.238C>G (p.Pro80Ala)	IGLL1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1348438	NM_020070.4(IGLL1):c.288T>G (p.His96Gln)	IGLL1	Uncertain significance	criteria provided, single submitter
1355401	NM_020070.4(IGLL1):c.203G>A (p.Gly68Asp)	IGLL1	Uncertain significance	criteria provided, single submitter
1356613	NM_020070.4(IGLL1):c.335C>A (p.Ala112Asp)	IGLL1	Uncertain significance	criteria provided, single submitter
1359833	NM_020070.4(IGLL1):c.26dup (p.Leu10fs)	IGLL1	Uncertain significance	criteria provided, single submitter
1363505	NM_020070.4(IGLL1):c.590T>G (p.Met197Arg)	IGLL1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
IGLL1	Strong	Autosomal recessive	agammaglobulinemia 2, autosomal recessive	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IGLL1	Orphanet:33110	Autosomal non-syndromic agammaglobulinemia

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
IGLL1	HGNC:5870	ENSG00000128322	P15814	Immunoglobulin lambda-like polypeptide 1	gencc,clinvar
C22orf15	HGNC:15558	ENSG00000169314	Q8WYQ4	Uncharacterized protein C22orf15	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IGLL1	Immunoglobulin lambda-like polypeptide 1	Critical for B-cell development.

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
Antibody/Immunoglobulin	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IGLL1	Antibody/Immunoglobulin	yes		Ig/MHC_CS, Ig_C1-set, Ig-like_dom
C22orf15	Other/Unknown	no		CXorf65-like

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
male germ line stem cell (sensu Vertebrata) in testis	2
bone marrow	1
bone marrow cell	1
olfactory segment of nasal mucosa	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IGLL1	112	tissue_specific	marker	bone marrow, bone marrow cell, male germ line stem cell (sensu Vertebrata) in testis
C22orf15	123		marker	right uterine tube, olfactory segment of nasal mucosa, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IGLL1	1,349
C22orf15	152

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IGLL1	P15814	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
C22orf15	Q8WYQ4	76.10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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
Cell surface interactions at the vascular wall	1	95.2×	0.011	IGLL1

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
immunoglobulin mediated immune response	1	702.2×	0.003	IGLL1
immune response	1	47.1×	0.021	IGLL1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
IGLL1	0	0
C22orf15	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	IGLL1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	C22orf15

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
IGLL1	0	—
C22orf15	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.