combined immunodeficiency due to MALT1 deficiency

Summary

combined immunodeficiency due to MALT1 deficiency (MONDO:0014197) is a disease caused by MALT1 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MALT1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 446

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	combined immunodeficiency due to MALT1 deficiency
Mondo ID	MONDO:0014197
OMIM	615468
Orphanet	397964
DOID	DOID:0111988
UMLS	C3809583
MedGen	815913
GARD	0017647
Is cancer (heuristic)	no

Also known as: combined immunodeficiency due to MALT1 deficiency · IMD12 · immunodeficiency 12 · immunodeficiency type 12

Data availability: 446 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 › combined immunodeficiency due to MALT1 deficiency

Related subtypes (32): ataxia telangiectasia, combined immunodeficiency due to ZAP70 deficiency, X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia, combined immunodeficiency due to moesin deficiency, Wiskott-Aldrich syndrome, MHC class I deficiency, combined immunodeficiency due to STK4 deficiency, combined immunodeficiency due to OX40 deficiency, combined immunodeficiency due to CD3gamma deficiency, combined immunodeficiency due to CTPS1 deficiency, combined immunodeficiency due to CRAC channel dysfunction, severe combined immunodeficiency, non-SCID combined immunodeficiency, combined immunodeficiency due to RELA haploinsufficiency, combined immunodeficiency due to GINS1 deficiency, combined immunodeficiency syndrome, combined immunodeficiency due to POLE2 deficiency, autosomal recessive combined immunodeficiency due to complete IL6ST deficiency, autosomal recessive combined immunodeficiency due to partial IL6ST deficiency, autosomal dominant combined immunodeficiency due to partial IL6ST deficiency, autosomal recessive combined immunodeficiency due to IL6R deficiency, autosomal dominant combined immunodeficiency due to ERBIN deficiency, combined immunodeficiency due to TBX1 deficiency, RAC2-related combined immunodeficiency-bronchiectasis-cancer-predisposing syndrome, combined immunodeficiency due to dimerization defective IKAROS mutation, late-onset combined immunodeficiency due to ICOSL deficiency, combined immunodeficiency-hypogammaglobulinemia-skeletal anomalies syndrome due to IKBKA deficiency, early-onset combined immunodeficiency with low ig due to dominant negative IKAROS mutation, combined immunodeficiency with low Ig due to BCL10 deficiency, IRF4-related combined immunodeficiency, NFATC1-related combined immunodeficiency, POLD3-related combined immunodeficiency

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

446 retrieved; paginated sample, class counts are floors:

226 likely benign, 165 uncertain significance, 20 benign, 15 pathogenic, 9 likely pathogenic, 5 conflicting classifications of pathogenicity, 4 benign/likely benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068658	NM_006785.4(MALT1):c.1356del (p.Glu453fs)	MALT1	Pathogenic	criteria provided, single submitter
1069927	NM_006785.4(MALT1):c.926_929delGAAG	MALT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
127139	NM_006785.4(MALT1):c.1739G>C (p.Trp580Ser)	MALT1	Pathogenic	no assertion criteria provided
1417195	NM_006785.4(MALT1):c.1318_1321del (p.Leu440fs)	MALT1	Pathogenic	criteria provided, single submitter
1454020	NM_006785.4(MALT1):c.818del (p.Lys273fs)	MALT1	Pathogenic	criteria provided, single submitter
1458444	NM_006785.4(MALT1):c.1661_1662insTTTTTTTTTTTTTTTTTNNNNNNNNNNGGCAGGGAGGTTGCAGTGAGCCGAGATGGCAGCAGTACAGTCCAGCTTCGGCTCCGCATGAGAGGGAGACCGTGGGGAGAGGGAGACAGAGCTCGAAGTAGTTT (p.Leu554delinsPhePhePhePhePhePheXaaXaaXaaXaaAlaGlyArgLeuGlnTer)	MALT1	Pathogenic	criteria provided, single submitter
1459602	NC_000018.9:g.(?56338876)(56339104_?)del	MALT1	Pathogenic	criteria provided, single submitter
2091535	NM_006785.4(MALT1):c.1504C>T (p.Gln502Ter)	MALT1	Pathogenic	criteria provided, single submitter
2853331	NM_006785.4(MALT1):c.594del (p.Phe198fs)	MALT1	Pathogenic	criteria provided, single submitter
2863299	NM_006785.4(MALT1):c.1551_1554del (p.Arg518fs)	MALT1	Pathogenic	criteria provided, single submitter
3723656	NM_006785.4(MALT1):c.305_306del (p.Thr102fs)	MALT1	Pathogenic	criteria provided, multiple submitters, no conflicts
636343	NM_006785.4(MALT1):c.571C>T (p.Arg191Ter)	MALT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
66089	NM_006785.4(MALT1):c.266G>T (p.Ser89Ile)	MALT1	Pathogenic	no assertion criteria provided
662739	NM_006785.4(MALT1):c.611dup (p.Gln205fs)	MALT1	Pathogenic	criteria provided, single submitter
831577	NC_000018.10:g.(?58671624)(58747862_?)del	MALT1	Pathogenic	criteria provided, single submitter
935699	NM_006785.4(MALT1):c.1321del (p.Cys441fs)	MALT1	Pathogenic	criteria provided, single submitter
971304	NM_006785.4(MALT1):c.596_599dup (p.Phe200fs)	MALT1	Pathogenic	criteria provided, single submitter
1067741	NM_006785.4(MALT1):c.986-1G>C	MALT1	Likely pathogenic	criteria provided, single submitter
1466078	NM_006785.4(MALT1):c.1475+1G>A	MALT1	Likely pathogenic	criteria provided, single submitter
1497535	NM_006785.4(MALT1):c.926-1G>A	MALT1	Likely pathogenic	criteria provided, single submitter
1526198	NM_006785.4(MALT1):c.1950del (p.Pro651fs)	MALT1	Likely pathogenic	criteria provided, single submitter
242617	NM_006785.3(MALT1):c.1019-2A>G	MALT1	Likely pathogenic	criteria provided, single submitter
2797070	NM_006785.4(MALT1):c.1911+1G>T	MALT1	Likely pathogenic	criteria provided, single submitter
3255329	NM_006785.4(MALT1):c.550G>T (p.Asp184Tyr)	MALT1	Likely pathogenic	criteria provided, single submitter
3583378	NM_006785.4(MALT1):c.886C>T (p.Arg296Ter)	MALT1	Likely pathogenic	criteria provided, single submitter
4735873	NM_006785.4(MALT1):c.949_958+73del	MALT1	Likely pathogenic	criteria provided, single submitter
1031678	NM_006785.4(MALT1):c.1401-15G>T	MALT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1437910	NM_006785.4(MALT1):c.2333A>G (p.His778Arg)	MALT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1562742	NM_006785.4(MALT1):c.502C>A (p.Pro168Thr)	MALT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
474596	NM_006785.4(MALT1):c.649+9C>T	MALT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

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
MALT1	Strong	Autosomal recessive	combined immunodeficiency due to MALT1 deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MALT1	Orphanet:397964	Combined immunodeficiency due to MALT1 deficiency
MALT1	Orphanet:52417	MALT lymphoma

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
MALT1	HGNC:6819	ENSG00000172175	Q9UDY8	Mucosa-associated lymphoid tissue lymphoma translocation protein 1	gencc,clinvar
ALPK2	HGNC:20565	ENSG00000198796	Q86TB3	Alpha-protein kinase 2	clinvar
MALT1-AS1	HGNC:55306	ENSG00000267226		MALT1 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MALT1	Mucosa-associated lymphoid tissue lymphoma translocation protein 1	Protease that enhances BCL10-induced activation: acts via formation of CBM complexes that channel adaptive and innate immune signaling downstream of CARD domain-containing proteins (CARD9, CARD11 and CARD14) to activate NF-kappa-B and MAP…
ALPK2	Alpha-protein kinase 2	Protein kinase that recognizes phosphorylation sites in which the surrounding peptides have an alpha-helical conformation.

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
Antibody/Immunoglobulin	1	9.7×	0.157
Kinase	1	9.2×	0.157
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MALT1	Antibody/Immunoglobulin	yes		Pept_C14_p20, Ig_sub2, Ig_sub
ALPK2	Kinase	yes		Ig_sub2, Ig_sub, a-kinase_dom
MALT1-AS1	Other/Unknown	no

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	2
colonic epithelium	1
tonsil	1
cardiac muscle of right atrium	1
left ventricle myocardium	1
myocardium	1
primordial germ cell in gonad	1
thymus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MALT1	275	ubiquitous	marker	colonic epithelium, tonsil, male germ line stem cell (sensu Vertebrata) in testis
ALPK2	147	ubiquitous	marker	left ventricle myocardium, cardiac muscle of right atrium, myocardium
MALT1-AS1	123		yes	thymus, primordial germ cell in gonad, 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
MALT1	1,852
ALPK2	371
MALT1-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MALT1	Q9UDY8	26

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ALPK2	Q86TB3	40.99

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
CLEC7A/inflammasome pathway	1	1903.3×	0.007	MALT1
Downstream signaling events of B Cell Receptor (BCR)	1	815.7×	0.008	MALT1
TCR signaling	1	496.5×	0.009	MALT1
Signaling by the B Cell Receptor (BCR)	1	346.1×	0.009	MALT1
Fc epsilon receptor (FCERI) signaling	1	271.9×	0.009	MALT1
C-type lectin receptors (CLRs)	1	237.9×	0.009	MALT1
Activation of NF-kappaB in B cells	1	196.9×	0.009	MALT1
FCERI mediated NF-kB activation	1	156.4×	0.010	MALT1
CLEC7A (Dectin-1) signaling	1	142.8×	0.010	MALT1
Downstream TCR signaling	1	128.3×	0.010	MALT1
Adaptive Immune System	1	29.8×	0.040	MALT1
Innate Immune System	1	25.5×	0.042	MALT1
Immune System	1	13.0×	0.077	MALT1

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
negative regulation of Wnt signaling pathway involved in heart development	1	8426.0×	0.002	ALPK2
B-1 B cell differentiation	1	4213.0×	0.002	MALT1
epicardium morphogenesis	1	4213.0×	0.002	ALPK2
regulation of apoptotic process	2	83.4×	0.002	MALT1, ALPK2
positive regulation of T-helper 17 cell differentiation	1	2808.7×	0.002	MALT1
response to fungus	1	2106.5×	0.002	MALT1
regulation of T cell receptor signaling pathway	1	2106.5×	0.002	MALT1
nuclear export	1	766.0×	0.004	MALT1
positive regulation of T cell cytokine production	1	648.1×	0.004	MALT1
cardiac muscle cell development	1	312.1×	0.008	ALPK2
lipopolysaccharide-mediated signaling pathway	1	263.3×	0.008	MALT1
obsolete proteolysis involved in protein catabolic process	1	263.3×	0.008	MALT1
positive regulation of interleukin-2 production	1	234.1×	0.008	MALT1
B cell activation	1	227.7×	0.008	MALT1
establishment of cell polarity	1	191.5×	0.008	ALPK2
T cell proliferation	1	191.5×	0.008	MALT1
heart morphogenesis	1	187.2×	0.008	ALPK2
positive regulation of interleukin-1 beta production	1	129.6×	0.011	MALT1
defense response	1	108.0×	0.012	MALT1
positive regulation of protein ubiquitination	1	106.7×	0.012	MALT1
T cell receptor signaling pathway	1	75.9×	0.016	MALT1
regulation of gene expression	1	41.7×	0.028	ALPK2
positive regulation of canonical NF-kappaB signal transduction	1	36.3×	0.031	MALT1
negative regulation of apoptotic process	1	17.4×	0.059	MALT1
proteolysis	1	17.1×	0.059	MALT1
innate immune response	1	16.8×	0.059	MALT1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
MALT1	MEPAZINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MALT1	5	4
ALPK2	0	0
MALT1-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MEPAZINE	4	MALT1
THIORIDAZINE	4	MALT1
PROMAZINE	4	MALT1
LAPACHONE	2	MALT1
SAFIMALTIB	2	MALT1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MALT1	130	Binding:128, Functional:2

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
MALT1	130

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

5 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.

Compound	Max phase	Cohort target (bioactivity)
MEPAZINE	4	MALT1
THIORIDAZINE	4	MALT1
PROMAZINE	4	MALT1
LAPACHONE	2	MALT1
SAFIMALTIB	2	MALT1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MALT1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ALPK2
E	Difficult family or no structure, no drug	1	MALT1-AS1

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)
ALPK2	0	—
MALT1-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.