On this page
MALT1
MALT1 paracaspase
MALT1 is located on the long (q) arm of chromosome 18, at band 18q21.32. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 18 in the library →Available at Jeen Health
Clinical tests that include this
Overview
MALT1 (MALT1 paracaspase) is located on chromosome 18 at position 18q21.32 and encodes a 824-amino acid protein that belongs to a rare class of enzymes called paracaspases. Unlike classical caspases, which are primarily involved in programmed cell death, MALT1 functions as both a signalling scaffold and a protease to coordinate immune responses. The protein is particularly important in lymphocytes, where it helps transmit signals from cell-surface receptors to the nucleus, enabling appropriate immune activation.
MALT1 is critical for the activation of nuclear factor kappa B (NF-κB), a master regulator of immune and inflammatory responses. Through its dual scaffold and enzymatic activities, MALT1 helps ensure that lymphocytes can mount effective responses against bacterial, viral, and fungal pathogens. Pathogenic variants in this gene can result in combined immunodeficiency, leaving affected individuals vulnerable to recurrent and severe infections.
What the gene does
The MALT1 protein functions as a molecular scaffold that brings together multiple signalling components within immune cells, whilst also acting as a protease that cleaves specific substrate proteins to amplify activation signals. When antigen receptors on the surface of T cells or B cells are engaged, MALT1 forms a complex with two other proteins, BCL10 and CARD11, creating what is known as the CBM signalosome. This complex is essential for transmitting signals from the cell surface to the nucleus.
MALT1's protease activity is particularly important for cleaving proteins that normally inhibit NF-κB signalling, thereby releasing this transcription factor to enter the nucleus and activate genes involved in immune cell proliferation, survival, and cytokine production. The enzyme also processes other substrates involved in regulating the magnitude and duration of immune responses. Beyond its role in antigen receptor signalling, MALT1 contributes to signalling pathways activated by pattern recognition receptors that detect microbial components.
The protein's scaffold function enables it to coordinate the assembly of signalling complexes even in the absence of its protease activity, highlighting the importance of its structural domains in organising cellular responses. This dual functionality makes MALT1 a central node in immune cell activation, with both functions necessary for robust immune defence.
Video: Genetics 101
Chromosome location
The MALT1 gene is located on the long arm of chromosome 18 at cytogenetic band 18q21.32. This chromosomal region contains several genes involved in immune function and cellular signalling. The genomic organisation of MALT1 includes multiple exons that encode the various functional domains of the protein, allowing for regulated expression in immune tissues.
Protein structure
The MALT1 protein comprises 824 amino acids organised into several distinct functional domains. The N-terminal region contains a Death domain (amino acids 39-126), which mediates protein-protein interactions necessary for assembly of signalling complexes. This is followed by two tandem Ig-like C2-type domains (amino acids 125-201 and 212-305), which contribute to the protein's scaffold function and help position substrates for cleavage.
The central portion of the protein contains a Caspase-like region (amino acids 348-562) that harbours the catalytic paracaspase activity, enabling MALT1 to cleave specific protein substrates. Although structurally similar to caspases, this domain has evolved distinct substrate specificity suited to immune signalling rather than apoptosis. A Nuclear export signal motif (amino acids 369-376) helps regulate the protein's subcellular localisation. The N-terminal region also includes a short Disordered segment (amino acids 1-27), which may provide flexibility for protein interactions and conformational changes during signalling complex assembly.
Key variants
Pathogenic variants in MALT1 are typically inherited in an autosomal recessive pattern, meaning that affected individuals carry alterations in both copies of the gene. These variants can include missense changes that disrupt either the scaffold or protease functions of the protein, as well as nonsense or frameshift variants that result in truncated, non-functional protein products. The severity of immune deficiency often correlates with the degree to which variants impair MALT1's dual functions in lymphocyte activation.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.305_306del | p.Thr102fs | Pathogenic | ★★☆☆ | Combined immunodeficiency due to MALT1 deficiency |
c.571C>T | p.Arg191Ter | Pathogenic | ★★☆☆ | Combined immunodeficiency due to MALT1 deficiency |
c.926_929delGAAG | - | Pathogenic/Likely pathogenic | ★★☆☆ | Combined immunodeficiency due to MALT1 deficiency |
g.(?_56338696)_(56421710_?)del | - | Pathogenic | ★☆☆☆ | Combined immunodeficiency due to MALT1 deficiency |
g.(?_56338876)_(56339104_?)del | - | Pathogenic | ★☆☆☆ | Combined immunodeficiency due to MALT1 deficiency |
c.1504C>T | p.Gln502Ter | Pathogenic | ★☆☆☆ | Combined immunodeficiency due to MALT1 deficiency |
c.1551_1554del | p.Arg518fs | Pathogenic | ★☆☆☆ | Combined immunodeficiency due to MALT1 deficiency |
c.1651C>T | p.Arg551Ter | Pathogenic | ★☆☆☆ | not provided |
c.1661_1662insTTTTTTTTTTTTTTTTTNNNNNNNNNNGGCAGGGAGGTTGCAGTGAGCCGAGATGGCAGCAGTACAGTCCAGCTTCGGCTCCGCATGAGAGGGAGACCGTGGGGAGAGGGAGACAGAGCTCGAAGTAGTTT | p.Leu554delinsPhePhePhePhePhePheXaaXaaXaaXaaAlaGlyArgLeuGlnTer | Pathogenic | ★☆☆☆ | Combined immunodeficiency due to MALT1 deficiency |
c.594del | p.Phe198fs | Pathogenic | ★☆☆☆ | Combined immunodeficiency due to MALT1 deficiency |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Bi-allelic pathogenic variants in MALT1 cause a form of combined immunodeficiency characterised by recurrent bacterial, viral, and fungal infections from early childhood. Affected individuals typically present with chronic diarrhoea, respiratory infections, skin infections, and failure to thrive. The immunodeficiency results from impaired activation of both T cells and B cells, which depend on MALT1-mediated signalling to respond effectively to pathogens. Laboratory findings often include reduced numbers of memory T cells and impaired antibody responses, reflecting the broad impact of MALT1 dysfunction on adaptive immunity. Early diagnosis through genetic testing can help guide immunological monitoring and infection prevention strategies.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic MALT1 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
MALT1 is included on the NHS Genomic Medicine Service panel for Primary immunodeficiency or monogenic inflammatory bowel disease (green classification, R15), reflecting its established role in heritable immune disorders. The gene also appears on the COVID-19 research panel (green classification), where it has been evaluated in the context of immune responses to viral infection. Green classification indicates strong evidence supporting the gene-disease relationship, making MALT1 testing appropriate for individuals with clinical features of combined immunodeficiency.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What inheritance pattern is associated with MALT1-related conditions?
MALT1-related immunodeficiency follows an autosomal recessive inheritance pattern, meaning an individual must inherit a pathogenic variant from both parents to develop the condition. Parents who each carry one altered copy are typically unaffected.
How does MALT1 differ from other caspase enzymes?
MALT1 is a paracaspase, a unique class of protease that shares structural similarity with caspases but has evolved distinct substrate specificity for immune signalling proteins rather than mediating cell death. It also functions as a scaffold protein, a role not typically associated with classical caspases.
Can MALT1 testing help diagnose unexplained immune deficiency?
Genetic testing for MALT1 variants can be valuable in individuals with combined immunodeficiency, particularly when accompanied by recurrent infections, chronic diarrhoea, and laboratory evidence of impaired T-cell and B-cell function. Testing is typically arranged through specialist immunology services.