Immunodeficiency, common variable, 4

Summary

Immunodeficiency, common variable, 4 (MONDO:0013284) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 195

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency, common variable, 4
Mondo ID	MONDO:0013284
OMIM	613494
Orphanet	696925
DOID	DOID:0081147
UMLS	C3150739
MedGen	462089
GARD	0015669
Is cancer (heuristic)	no

Also known as: CVID4 · immunodeficiency, common variable, 4 · immunodeficiency, common variable, type 4

Data availability: 195 ClinVar variants · 3 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, 4

Related subtypes (15): immune deficiency, familial variable, immunodeficiency, common variable, 2, immunodeficiency, common variable, 1, immunodeficiency, common variable, 3, 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, 14, 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

195 retrieved; paginated sample, class counts are floors:

108 uncertain significance, 63 likely benign, 14 conflicting classifications of pathogenicity, 4 benign, 4 benign/likely benign, 1 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4459	NM_052945.4(TNFRSF13C):c.265_288del (p.Leu89_Val96del)	TNFRSF13C	Pathogenic	no assertion criteria provided
2434179	NM_052945.4(TNFRSF13C):c.154G>A (p.Ala52Thr)	LOC130067574	Likely pathogenic	criteria provided, single submitter
341877	NM_052945.4(TNFRSF13C):c.317G>A (p.Arg106Gln)	LOC130067574	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341878	NM_052945.4(TNFRSF13C):c.288G>A (p.Val96=)	LOC130067574	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341883	NM_052945.4(TNFRSF13C):c.62C>G (p.Pro21Arg)	LOC130067574	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
440343	NM_052945.4(TNFRSF13C):c.191G>T (p.Gly64Val)	LOC130067574	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
538823	NM_052945.4(TNFRSF13C):c.213G>A (p.Ala71=)	LOC130067574	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
785729	NM_052945.4(TNFRSF13C):c.246C>T (p.Pro82=)	LOC130067574	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
900263	NM_052945.4(TNFRSF13C):c.307C>A (p.Arg103=)	LOC130067574	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1461158	NM_052945.4(TNFRSF13C):c.431C>T (p.Ala144Val)	TNFRSF13C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341879	NM_052945.4(TNFRSF13C):c.255G>C (p.Leu85=)	TNFRSF13C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
440344	NM_052945.4(TNFRSF13C):c.60C>T (p.Val20=)	TNFRSF13C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
440345	NM_052945.4(TNFRSF13C):c.475C>T (p.His159Tyr)	TNFRSF13C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
717071	NM_052945.4(TNFRSF13C):c.436C>T (p.Pro146Ser)	TNFRSF13C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
728274	NM_052945.4(TNFRSF13C):c.375G>A (p.Glu125=)	TNFRSF13C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
900261	NM_052945.4(TNFRSF13C):c.368-15C>A	TNFRSF13C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
538825	NC_000022.11:g.(?41301335)(42070317_?)del	ACO2	Uncertain significance	criteria provided, single submitter
1009610	NM_052945.4(TNFRSF13C):c.264_275dup (p.88ALVL[3])	LOC130067574	Uncertain significance	criteria provided, single submitter
1018789	NM_052945.4(TNFRSF13C):c.89G>A (p.Arg30His)	LOC130067574	Uncertain significance	criteria provided, single submitter
1053269	NM_052945.4(TNFRSF13C):c.224C>A (p.Pro75His)	LOC130067574	Uncertain significance	criteria provided, single submitter
1059823	NM_052945.4(TNFRSF13C):c.264_265insATGGTCCTGGCG (p.Ala88_Leu89insMetValLeuAla)	LOC130067574	Uncertain significance	criteria provided, single submitter
1060107	NM_052945.4(TNFRSF13C):c.11G>A (p.Gly4Glu)	LOC130067574	Uncertain significance	criteria provided, single submitter
1061017	NM_052945.4(TNFRSF13C):c.226G>T (p.Gly76Trp)	LOC130067574	Uncertain significance	criteria provided, single submitter
1357103	NM_052945.4(TNFRSF13C):c.331G>T (p.Ala111Ser)	LOC130067574	Uncertain significance	criteria provided, single submitter
1392259	NM_052945.4(TNFRSF13C):c.14C>A (p.Pro5His)	LOC130067574	Uncertain significance	criteria provided, single submitter
1405370	NM_052945.4(TNFRSF13C):c.275_286dup (p.88ALVL[3])	LOC130067574	Uncertain significance	criteria provided, single submitter
1419262	NM_052945.4(TNFRSF13C):c.35A>G (p.Asp12Gly)	LOC130067574	Uncertain significance	criteria provided, single submitter
1441522	NM_052945.4(TNFRSF13C):c.142G>A (p.Ala48Thr)	LOC130067574	Uncertain significance	criteria provided, single submitter
1470219	NM_052945.4(TNFRSF13C):c.238G>A (p.Gly80Ser)	LOC130067574	Uncertain significance	criteria provided, single submitter
1476123	NM_052945.4(TNFRSF13C):c.326GCG[3] (p.Gly110dup)	LOC130067574	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
TNFRSF13C	Moderate	Autosomal recessive	immunodeficiency, common variable, 4	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TNFRSF13C	Orphanet:696925	Adult-onset common variable immunodeficiency due to BAFF-receptor deficiency
ACO2	Orphanet:313850	Infantile cerebellar-retinal degeneration
ACO2	Orphanet:98676	Autosomal recessive isolated optic atrophy
NAGA	Orphanet:79279	Alpha-N-acetylgalactosaminidase deficiency type 1
NAGA	Orphanet:79280	Alpha-N-acetylgalactosaminidase deficiency type 2
NAGA	Orphanet:79281	Alpha-N-acetylgalactosaminidase deficiency type 3

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
TNFRSF13C	HGNC:17755	ENSG00000159958	Q96RJ3	Tumor necrosis factor receptor superfamily member 13C	gencc,clinvar
ACO2	HGNC:118	ENSG00000100412	Q99798	Aconitate hydratase, mitochondrial	clinvar
NAGA	HGNC:7631	ENSG00000198951	P17050	Alpha-N-acetylgalactosaminidase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TNFRSF13C	Tumor necrosis factor receptor superfamily member 13C	B-cell receptor specific for TNFSF13B/TALL1/BAFF/BLyS.
ACO2	Aconitate hydratase, mitochondrial	Catalyzes the isomerization of citrate to isocitrate via cis-aconitate.
NAGA	Alpha-N-acetylgalactosaminidase	Removes terminal alpha-N-acetylgalactosamine residues from glycolipids and glycopeptides.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
Enzyme (other)	2	8.0×	0.039
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TNFRSF13C	Other/Unknown	no		TNFR_13C_TALL-1-bd, TNFR_13C, TNFR_13C/17
ACO2	Enzyme (other)	yes	4.2.1.3	AconitaseA/IPMdHydase_ssu_swvl, Acoase/IPM_deHydtase_lsu_aba, Aconitase_mito-like
NAGA	Enzyme (other)	yes	3.2.1.49	Glyco_hydro_27/36_CS, Glyco_hydro_27, Glyco_hydro_b

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
lymph node	1
spleen	1
vermiform appendix	1
apex of heart	1
heart right ventricle	1
left ventricle myocardium	1
leukocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TNFRSF13C	151	broad	marker	spleen, lymph node, vermiform appendix
ACO2	291	ubiquitous	marker	heart right ventricle, apex of heart, left ventricle myocardium
NAGA	252	ubiquitous	marker	monocyte, mononuclear cell, leukocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACO2	4,776
TNFRSF13C	1,443
NAGA	1,327

Intra-cohort edges

A	B	Sources
ACO2	NAGA	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TNFRSF13C	Q96RJ3	8
NAGA	P17050	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACO2	Q99798	95.44

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway	1	335.9×	0.016	TNFRSF13C
Maturation of TCA enzymes and regulation of TCA cycle	1	285.5×	0.016	ACO2
Citric acid cycle (TCA cycle)	1	211.5×	0.016	ACO2
Protein localization	1	95.2×	0.020	ACO2
TNFR2 non-canonical NF-kB pathway	1	90.6×	0.020	TNFRSF13C
Mitochondrial protein import	1	84.0×	0.020	ACO2
Mitochondrial protein degradation	1	57.1×	0.025	ACO2
Aerobic respiration and respiratory electron transport	1	44.3×	0.028	ACO2
Metabolism of proteins	1	6.2×	0.165	ACO2
Metabolism	1	5.8×	0.165	ACO2

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
glycolipid catabolic process	1	2808.7×	0.003	NAGA
B cell costimulation	1	1872.4×	0.003	TNFRSF13C
citrate metabolic process	1	1404.3×	0.003	ACO2
carbohydrate catabolic process	1	1123.5×	0.003	NAGA
glycoside catabolic process	1	936.2×	0.003	NAGA
oligosaccharide metabolic process	1	234.1×	0.009	NAGA
tricarboxylic acid cycle	1	170.2×	0.011	ACO2
T cell costimulation	1	124.8×	0.011	TNFRSF13C
generation of precursor metabolites and energy	1	114.6×	0.011	ACO2
positive regulation of B cell proliferation	1	114.6×	0.011	TNFRSF13C
tumor necrosis factor-mediated signaling pathway	1	110.1×	0.011	TNFRSF13C
positive regulation of T cell proliferation	1	86.4×	0.012	TNFRSF13C
adaptive immune response	1	28.1×	0.035	TNFRSF13C

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TNFRSF13C	0	0
ACO2	0	0
NAGA	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
NAGA	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ACO2	4.2.1.3	aconitate hydratase
NAGA	3.2.1.49	alpha-N-acetylgalactosaminidase

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	NAGA
D	Druggable family + AlphaFold only, no drug	1	ACO2
E	Difficult family or no structure, no drug	1	TNFRSF13C

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)
TNFRSF13C	0	—
ACO2	0	—
NAGA	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.