Immunodeficiency, common variable, 14

Summary

Immunodeficiency, common variable, 14 (MONDO:0054691) is a disease caused by IRF2BP2 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: IRF2BP2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 34

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency, common variable, 14
Mondo ID	MONDO:0054691
OMIM	617765
Orphanet	696904
DOID	DOID:0081156
UMLS	C4540380
MedGen	1614928
GARD	0025961
Is cancer (heuristic)	no

Also known as: CVID14 · immunodeficiency, common variable, 14

Data availability: 34 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic agammaglobulinemia › common variable immunodeficiency › immunodeficiency, common variable, 14

Related subtypes (15): immune deficiency, familial variable, immunodeficiency, common variable, 2, immunodeficiency, common variable, 1, immunodeficiency, common variable, 3, immunodeficiency, common variable, 4, immunodeficiency, common variable, 5, immunodeficiency, common variable, 6, immunodeficiency, common variable, 7, combined immunodeficiency due to LRBA deficiency, immunodeficiency, common variable, 10, IL21-related infantile inflammatory bowel disease, immunodeficiency, common variable, 12, pancytopenia due to IKZF1 mutations, immunodeficiency, common variable, due to APRIL deficiency, immunodeficiency, common variable, 15

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

34 retrieved; paginated sample, class counts are floors:

19 uncertain significance, 4 benign, 3 likely pathogenic, 2 conflicting classifications of pathogenicity, 2 pathogenic, 2 benign/likely benign, 1 no classifications from unflagged records, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2577840	NC_000001.11:g.(233502994_233518999)_(236093155_236105019)del	ARID4B	Pathogenic	no assertion criteria provided
4820101	NC_000001.11:g.234258308_236349718del	ARID4B	Pathogenic	criteria provided, single submitter
2577020	NM_182972.3(IRF2BP2):c.314_324del (p.Glu105fs)	IRF2BP2	Likely pathogenic	no assertion criteria provided
2577035	NM_182972.3(IRF2BP2):c.217_244del (p.Pro73fs)	IRF2BP2	Likely pathogenic	no assertion criteria provided
3362908	NM_182972.3(IRF2BP2):c.1137G>A (p.Trp379Ter)	IRF2BP2	Likely pathogenic	criteria provided, single submitter
2431683	NM_182972.3(IRF2BP2):c.124_147del (p.Asn42_Val49del)	IRF2BP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
636927	NM_182972.3(IRF2BP2):c.352C>G (p.Pro118Ala)	IRF2BP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030390	NM_182972.3(IRF2BP2):c.451C>A (p.Pro151Thr)	IRF2BP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1030391	NM_182972.3(IRF2BP2):c.535C>G (p.Arg179Gly)	IRF2BP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1031779	NM_182972.3(IRF2BP2):c.344A>G (p.Glu115Gly)	IRF2BP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1334087	NM_182972.3(IRF2BP2):c.1330G>A (p.Ala444Thr)	IRF2BP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1448760	NM_182972.3(IRF2BP2):c.189C>A (p.His63Gln)	IRF2BP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1475068	NM_182972.3(IRF2BP2):c.626C>G (p.Ala209Gly)	IRF2BP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1521981	NM_182972.3(IRF2BP2):c.6_11dup (p.Ala3_Ala4dup)	IRF2BP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1525908	NM_182972.3(IRF2BP2):c.289C>G (p.Gln97Glu)	IRF2BP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1896379	NM_182972.3(IRF2BP2):c.737C>T (p.Ala246Val)	IRF2BP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1940230	NM_182972.3(IRF2BP2):c.1164G>C (p.Lys388Asn)	IRF2BP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2431892	NM_182972.3(IRF2BP2):c.1727C>T (p.Ala576Val)	IRF2BP2	Uncertain significance	criteria provided, single submitter
2432866	NM_182972.3(IRF2BP2):c.1606C>T (p.Gln536Ter)	IRF2BP2	Uncertain significance	criteria provided, single submitter
2577526	NM_182972.3(IRF2BP2):c.314_324dup (p.Ala110fs)	IRF2BP2	Uncertain significance	criteria provided, single submitter
2585532	NM_182972.3(IRF2BP2):c.1520C>T (p.Thr507Ile)	IRF2BP2	Uncertain significance	criteria provided, single submitter
3008618	NM_182972.3(IRF2BP2):c.627_659del (p.Ala214_Leu224del)	IRF2BP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3377690	NM_182972.3(IRF2BP2):c.653G>C (p.Gly218Ala)	IRF2BP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3624281	NM_182972.3(IRF2BP2):c.1042A>G (p.Lys348Glu)	IRF2BP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3897980	NM_182972.3(IRF2BP2):c.1344C>G (p.His448Gln)	IRF2BP2	Uncertain significance	criteria provided, single submitter
446216	NM_182972.3(IRF2BP2):c.1652G>A (p.Ser551Asn)	IRF2BP2	no classifications from unflagged records	no classifications from unflagged records
811030	NM_182972.3(IRF2BP2):c.1180A>C (p.Thr394Pro)	IRF2BP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2920775	NM_182972.3(IRF2BP2):c.-4G>C	IRF2BP2	Benign	criteria provided, multiple submitters, no conflicts
402983	NM_182972.3(IRF2BP2):c.828G>T (p.Ala276=)	IRF2BP2	Benign	criteria provided, multiple submitters, no conflicts
402984	NM_182972.3(IRF2BP2):c.232T>C (p.Ser78Pro)	IRF2BP2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · 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
IRF2BP2	Strong	Autosomal dominant	immunodeficiency, common variable, 14	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IRF2BP2	Orphanet:520	Acute promyelocytic leukemia
IRF2BP2	Orphanet:696904	Common variable immunodeficiency phenotype due to IRF2BP2 deficiency

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
IRF2BP2	HGNC:21729	ENSG00000168264	Q7Z5L9	Interferon regulatory factor 2-binding protein 2	gencc,clinvar
ARID4B	HGNC:15550	ENSG00000054267	Q4LE39	AT-rich interactive domain-containing protein 4B	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IRF2BP2	Interferon regulatory factor 2-binding protein 2	Acts as a transcriptional corepressor in a IRF2-dependent manner; this repression is not mediated by histone deacetylase activities.
ARID4B	AT-rich interactive domain-containing protein 4B	Acts as a transcriptional repressor.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IRF2BP2	Transcription factor	no		IRF-2BP1_2-like_Znf, I2BP1/2_C3HC4-RING_sf, Zf-C3HC4_IRF-2BP1_2
ARID4B	Other/Unknown	no		ARID_dom, Tudor, ARID4A/B_PWWP

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
epithelium of mammary gland	1
mammary duct	1
trachea	1
choroid plexus epithelium	1
parietal pleura	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IRF2BP2	256	ubiquitous	marker	mammary duct, epithelium of mammary gland, trachea
ARID4B	291	ubiquitous	marker	choroid plexus epithelium, sperm, parietal pleura

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARID4B	3,755
IRF2BP2	1,162

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IRF2BP2	Q7Z5L9	3
ARID4B	Q4LE39	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. 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
Negative epigenetic regulation of rRNA expression	1	259.6×	0.024	ARID4B
HDACs deacetylate histones	1	120.2×	0.024	ARID4B
Potential therapeutics for SARS	1	114.2×	0.024	ARID4B
NoRC negatively regulates rRNA expression	1	104.8×	0.024	ARID4B
Chromatin organization	1	81.6×	0.024	ARID4B
Chromatin modifying enzymes	1	72.3×	0.024	ARID4B
Epigenetic regulation of gene expression	1	71.4×	0.024	ARID4B
SARS-CoV Infections	1	55.4×	0.027	ARID4B
Viral Infection Pathways	1	30.8×	0.043	ARID4B
Infectious disease	1	24.8×	0.048	ARID4B
Gene expression (Transcription)	1	17.8×	0.061	ARID4B
Disease	1	13.1×	0.076	ARID4B

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
establishment of Sertoli cell barrier	1	1685.2×	0.005	ARID4B
immature B cell differentiation	1	1203.7×	0.005	IRF2BP2
genomic imprinting	1	495.6×	0.008	ARID4B
negative regulation of stem cell population maintenance	1	383.0×	0.008	ARID4B
negative regulation of transcription by RNA polymerase II	2	17.7×	0.008	IRF2BP2, ARID4B
positive regulation of stem cell population maintenance	1	172.0×	0.012	ARID4B
regulation of transcription by RNA polymerase II	2	11.7×	0.013	IRF2BP2, ARID4B
negative regulation of transforming growth factor beta receptor signaling pathway	1	86.9×	0.017	ARID4B
negative regulation of cell migration	1	55.8×	0.024	ARID4B
transcription by RNA polymerase II	1	35.3×	0.034	ARID4B
spermatogenesis	1	17.6×	0.061	ARID4B
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	ARID4B

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IRF2BP2	0	0
ARID4B	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
IRF2BP2	1	Binding:1

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	IRF2BP2, ARID4B

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)
IRF2BP2	1	—
ARID4B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.