severe combined immunodeficiency due to CARD11 deficiency

Summary

severe combined immunodeficiency due to CARD11 deficiency (MONDO:0014081) is a disease caused by CARD11 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CARD11 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 1,222

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	severe combined immunodeficiency due to CARD11 deficiency
Mondo ID	MONDO:0014081
OMIM	615206
Orphanet	357237
DOID	DOID:0111957
UMLS	C3554686
MedGen	767600
GARD	0017549
Is cancer (heuristic)	no

Also known as: IMD11 · IMD11A · immunodeficiency 11 · immunodeficiency 11A · immunodeficiency type 11

Data availability: 1,222 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › combined immunodeficiency › severe combined immunodeficiency › T+ B+ severe combined immunodeficiency › severe combined immunodeficiency due to CARD11 deficiency

Related subtypes (1): severe combined immunodeficiency due to IKK2 deficiency

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

600 retrieved; paginated sample, class counts are floors:

321 likely benign, 195 uncertain significance, 38 conflicting classifications of pathogenicity, 22 benign, 13 pathogenic, 7 benign/likely benign, 4 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068965	NM_032415.7(CARD11):c.676C>T (p.Gln226Ter)	CARD11	Pathogenic	criteria provided, single submitter
1069758	NM_032415.7(CARD11):c.2062C>T (p.Arg688Ter)	CARD11	Pathogenic	criteria provided, single submitter
1070449	NM_032415.7(CARD11):c.793C>T (p.Gln265Ter)	CARD11	Pathogenic	criteria provided, single submitter
1070810	NM_032415.7(CARD11):c.2437G>T (p.Glu813Ter)	CARD11	Pathogenic	criteria provided, single submitter
1074577	NC_000007.13:g.(?2998114)(2998160_?)del	CARD11	Pathogenic	criteria provided, single submitter
1378516	NM_032415.7(CARD11):c.2650dup (p.Arg884fs)	CARD11	Pathogenic	criteria provided, single submitter
1451672	NM_032415.7(CARD11):c.799del (p.Leu267fs)	CARD11	Pathogenic	criteria provided, single submitter
1456913	NC_000007.13:g.(?2972149)(2972240_?)del	CARD11	Pathogenic	criteria provided, single submitter
183144	NM_032415.7(CARD11):c.368G>A (p.Gly123Asp)	CARD11	Pathogenic	criteria provided, single submitter
1995060	NM_032415.7(CARD11):c.2579del (p.Gly860fs)	CARD11	Pathogenic	criteria provided, single submitter
203461	NM_032415.7(CARD11):c.146G>A (p.Cys49Tyr)	CARD11	Pathogenic	criteria provided, single submitter
2043569	NM_032415.7(CARD11):c.1663del (p.Arg555fs)	CARD11	Pathogenic	criteria provided, single submitter
2931094	NM_032415.7(CARD11):c.2671C>T (p.Arg891Ter)	CARD11	Pathogenic	criteria provided, single submitter
1479301	NM_032415.7(CARD11):c.864+1G>A	CARD11	Likely pathogenic	criteria provided, single submitter
1521112	NM_032415.7(CARD11):c.1940+1G>T	CARD11	Likely pathogenic	criteria provided, single submitter
2930094	NM_032415.7(CARD11):c.1941-1G>T	CARD11	Likely pathogenic	criteria provided, single submitter
1174515	NM_032415.7(CARD11):c.377G>A (p.Gly126Asp)	CARD11-AS1	Likely pathogenic	criteria provided, single submitter
1010377	NM_032415.7(CARD11):c.2917C>T (p.Arg973Cys)	CARD11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1016705	NM_032415.7(CARD11):c.511G>A (p.Val171Met)	CARD11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1017453	NM_032415.7(CARD11):c.1740C>A (p.Asp580Glu)	CARD11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1017661	NM_032415.7(CARD11):c.752T>C (p.Leu251Pro)	CARD11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1020627	NM_032415.7(CARD11):c.2597G>A (p.Arg866Gln)	CARD11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1023980	NM_032415.7(CARD11):c.2239G>A (p.Val747Ile)	CARD11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030970	NM_032415.7(CARD11):c.2059G>A (p.Ala687Thr)	CARD11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1040363	NM_032415.7(CARD11):c.2711G>A (p.Ser904Asn)	CARD11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1043599	NM_032415.7(CARD11):c.2407G>A (p.Val803Ile)	CARD11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1055950	NM_032415.7(CARD11):c.2063G>A (p.Arg688Gln)	CARD11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1062525	NM_032415.7(CARD11):c.2006C>T (p.Thr669Met)	CARD11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1063627	NM_032415.7(CARD11):c.223C>T (p.Arg75Trp)	CARD11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1079640	NM_032415.7(CARD11):c.1342-4C>T	CARD11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 4 · 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
CARD11	Definitive	Autosomal recessive	severe combined immunodeficiency due to CARD11 deficiency	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CARD11	Orphanet:300324	Persistent polyclonal B-cell lymphocytosis
CARD11	Orphanet:357237	Combined immunodeficiency due to CARD11 deficiency
CARD11	Orphanet:464336	BENTA disease
CARD11	Orphanet:619972	CADINS disease

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CARD11	HGNC:16393	ENSG00000198286	Q9BXL7	Caspase recruitment domain-containing protein 11	gencc,clinvar
AMZ1	HGNC:22231	ENSG00000174945	Q400G9	Archaemetzincin-1	clinvar
CARD11-AS1	HGNC:40766	ENSG00000237286		CARD11 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CARD11	Caspase recruitment domain-containing protein 11	Adapter protein that plays a key role in adaptive immune response by transducing the activation of NF-kappa-B downstream of T-cell receptor (TCR) and B-cell receptor (BCR) engagement.
AMZ1	Archaemetzincin-1	Probable zinc metalloprotease.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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
Scaffold/PPI	1	5.8×	0.327
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CARD11	Scaffold/PPI	no		CARD, DEATH-like_dom_sf, P-loop_NTPase
AMZ1	Other/Unknown	no		Pept_M54_archaemetzincn, MetalloPept_cat_dom_sf, Archaemetzincin
CARD11-AS1	Other/Unknown	no

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	2
granulocyte	1
lymph node	1
spleen	1
amygdala	1
stromal cell of endometrium	1
bone marrow cell	1
colonic epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CARD11	188	broad	marker	granulocyte, lymph node, spleen
AMZ1	166	broad	yes	male germ line stem cell (sensu Vertebrata) in testis, amygdala, stromal cell of endometrium
CARD11-AS1	66		yes	male germ line stem cell (sensu Vertebrata) in testis, bone marrow cell, colonic epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CARD11	3,587
AMZ1	501
CARD11-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CARD11	Q9BXL7	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AMZ1	Q400G9	74.62

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 3 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
Downstream signaling events of B Cell Receptor (BCR)	1	815.7×	0.010	CARD11
TCR signaling	1	496.5×	0.010	CARD11
Signaling by the B Cell Receptor (BCR)	1	346.1×	0.010	CARD11
Fc epsilon receptor (FCERI) signaling	1	271.9×	0.010	CARD11
C-type lectin receptors (CLRs)	1	237.9×	0.010	CARD11
Activation of NF-kappaB in B cells	1	196.9×	0.010	CARD11
FCERI mediated NF-kB activation	1	156.4×	0.010	CARD11
CLEC7A (Dectin-1) signaling	1	142.8×	0.010	CARD11
Downstream TCR signaling	1	128.3×	0.010	CARD11
Adaptive Immune System	1	29.8×	0.040	CARD11
Innate Immune System	1	25.5×	0.043	CARD11
Immune System	1	13.0×	0.077	CARD11

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
thymic T cell selection	1	2808.7×	0.006	CARD11
CD4-positive, alpha-beta T cell proliferation	1	936.2×	0.006	CARD11
positive regulation of CD4-positive, alpha-beta T cell proliferation	1	842.6×	0.006	CARD11
regulation of B cell differentiation	1	648.1×	0.006	CARD11
regulation of T cell differentiation	1	601.9×	0.006	CARD11
TORC1 signaling	1	401.2×	0.007	CARD11
positive regulation of T cell receptor signaling pathway	1	383.0×	0.007	CARD11
homeostasis of number of cells	1	337.0×	0.007	CARD11
B cell proliferation	1	240.7×	0.008	CARD11
positive regulation of interleukin-2 production	1	234.1×	0.008	CARD11
T cell costimulation	1	187.2×	0.008	CARD11
canonical NF-kappaB signal transduction	1	183.2×	0.008	CARD11
positive regulation of B cell proliferation	1	172.0×	0.008	CARD11
B cell differentiation	1	109.4×	0.012	CARD11
obsolete positive regulation of NF-kappaB transcription factor activity	1	102.8×	0.012	CARD11
protein homooligomerization	1	61.1×	0.019	CARD11
regulation of apoptotic process	1	41.7×	0.027	CARD11
positive regulation of canonical NF-kappaB signal transduction	1	36.3×	0.029	CARD11
proteolysis	1	17.1×	0.058	AMZ1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
CARD11	0	0
AMZ1	0	0
CARD11-AS1	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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	CARD11, AMZ1, CARD11-AS1

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)
CARD11	0	—
AMZ1	0	—
CARD11-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.