MALT1

Chr 18AR

MALT1 paracaspase

Also known as: IMD12, MLT, MLT1, PCASP1

NCBI Gene: 10892 ENSG00000172175 UniProt: Q9UDY8 OMIM: 604860

This gene encodes a caspase-like protease that forms CBM signaling complexes to activate NF-κB and p38 MAP kinase pathways, promoting expression of pro-inflammatory cytokines and mediating T-cell receptor signaling and lymphocyte activation. Mutations cause immunodeficiency 12, an autosomal recessive primary immunodeficiency affecting adaptive and innate immune responses. The gene is highly constrained against loss-of-function variants (pLI 0.99, LOEUF 0.3), indicating that biallelic mutations causing severe protein disruption are likely pathogenic.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a caspase-like protease that plays a role in BCL10-induced activation of NF-kappaB. The protein is a component of the CARMA1-BCL10-MALT1 (CBM) signalosome that triggers NF-kappaB signaling and lymphoctye activation following antigen-receptor stimulation. Mutations in this gene result in immunodeficiency 12 (IMD12). This gene has been found to be recurrently rearranged in chromosomal translocations with other genes in mucosa-associated lymphoid tissue lymphomas, including a t(11;18)(q21;q21) translocation with the baculoviral IAP repeat-containing protein 3 (also known as apoptosis inhibitor 2) locus [BIRC3(API2)-MALT1], and a t(14;18)(q32;q21) translocation with the immunoglobulin heavy chain locus (IGH-MALT1). Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, May 2018]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Immunodeficiency 12MIM #615468

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · combined immunodeficiency due to MALT1 deficiency · AR · ClinGen 2022

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.30

LOEUF· LoF intol.

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.30LOEUF

pLI 0.987

Z-score 4.94

OE 0.15 (0.08–0.30)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.84Z-score

OE missense 0.59 (0.53–0.66)

229 obs / 385.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.15 (0.08–0.30)

0≤0.351.4

Missense OE?0.59 (0.53–0.66)

0≤0.61.4

Synonymous OE?0.85

0≤1.21.6

LoF obs/exp: 6 / 39.5Missense obs/exp: 229 / 385.9Syn Z: 1.35

Background carrier burden — how many people carry a rare variant somewhere in MALT1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 89

772 rare PASS variants

Rare truncating (LoF)

1 in 2,100

124 rare PASS variants

Rare synonymous (reference)

1 in 120

388 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MALT1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 100	1 in 2,700
South Asian	~43k	1 in 130	1 in 620
Remaining (unassigned)	~30k	1 in 67	1 in 2,700
European (Finnish)	~27k	1 in 260	1 in 4,200
Admixed American	~22k	1 in 91	1 in 850
African / African American	~21k	1 in 86	1 in 1,100
East Asian	~20k	1 in 89	≈ 1 in 4,600
Ashkenazi Jewish	~13k	1 in 250	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 82	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 9 of 17 coding exons well covered in gnomAD exomes; exon 8 poorly covered; exons 1, 3, 6, 7, 9 and 2 more marginal. Genomes: 16 of 17 (exon 3 below).? see exons ↓