NLRP1
protein-codingNLR family pyrin domain containing 1, the group of NLR family|Pyrin domain containing|Caspase recruitment domain containing
Gene summary
This gene encodes a member of the Ced-4 family of apoptosis proteins. Ced-family members contain a caspase recruitment domain (CARD) and are known to be key mediators of programmed cell death. The encoded protein contains a distinct N-terminal pyrin-like motif, which is possibly involved in protein-protein interactions. This protein interacts strongly with caspase 2 and weakly with caspase 9. Overexpression of this gene was demonstrated to induce apoptosis in cells. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene, but the biological validity of some variants has not been determined. [provided by RefSeq, Jul 2008]
- NALP1
- SLEV1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~120.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014089
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0014089
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0060457
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014089
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: SD
Disease ID:MONDO:0060457
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0060457
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0014089
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0060457
Submitter: PanelApp Australia
Inheritance Pattern: SD
Disease ID:MONDO:0014089
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0014089
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Dermatologic; Hematologic; Musculoskeletal; Oncologic; Ophthalmologic
Intervention: Hematologic; Oncologic
Rationale: Palmoplantar carcinoma involves recurrent palmoplantar, conjunctival, and corneal keratoacanthomas, and individuals have been described as having high susceptibility to malignant squamous cell carcinoma; Features of Autoinflammation with arthritis and dyskeratosis have been described as including anemia severe enough to necessitate splenectomy, and awareness may allow prompt diagnosis and management; Individuals were not reported to benefit from Vitamin A supplementation
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NLRP1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_033004.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 6 | 299 | 4 | 309 | ||
| missense | 3 | 2 | 638 | 58 | 701 | |
| nonsense | 29 | 29 | ||||
| start loss | 0 | |||||
| frameshift | 31 | 31 | ||||
| splice donor/acceptor (+/-2bp) | 18 | 18 | ||||
| Total | 3 | 2 | 722 | 357 | 4 | 1088 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_127497.1 | 17 | MANE Select | |
| Ensembl | ENSP00000460475.1 | 17 | MANE Select | |
| RefSeq | NP_001028225.1 | 16 | Standard | |
| RefSeq | NP_055737.1 | 16 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- NOD-like receptor signaling pathway - Homo sapiens (human)
- Nucleotide-binding Oligomerization Domain (NOD) pathway
- The NLRP1 inflammasome
- Inflammasomes
- Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways
Biological Process
- apoptotic process
- activation of cysteine-type endopeptidase activity involved in apoptotic process
- inflammatory response
- viral process
- response to muramyl dipeptide
Molecular Function
- protein binding
- ATP binding
- cysteine-type endopeptidase activator activity involved in apoptotic process
- enzyme binding
- protein domain specific binding
Cellular Component
- nucleus
- nucleoplasm
- cytosol
- inflammasome complex
- NLRP1 inflammasome complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000572272
- Coding exons
- 17
- Length
- 119998
- Individuals with no LoFs
- 125679
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 69
- Defined
- 125748
- p
- 0.000274
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.49 | 685 | 804 | 0.852 | 0.0000447 | 9517 |
| Missense (PolyPhen) | 148 | 213.78 | 0.69231 | 2890 | ||
| Synonymous | 0.621 | 323 | 338 | 0.957 | 0.0000195 | 2987 |
| Loss of Function | 2.60 | 39 | 60.9 | 0.640 | 0.00000303 | 686 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00013 | 0.00012 | rare |
| Latino/Admixed American | 0.00044 | 0.00043 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00076 | 0.00076 | rare |
| Finnish | 0.000093 | 0.000092 | rare |
| European (Non-Finnish) | 0.00026 | 0.00025 | rare |
| South Asian | 0.00017 | 0.00016 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: As the sensor component of the NLRP1 inflammasome, plays a crucial role in innate immunity and inflammation. In response to pathogens and other damage-associated signals, initiates the formation of the inflammasome polymeric complex, made of NLRP1, CASP1, and possibly PYCARD. Recruitment of proCASP1 to the inflammasome promotes its activation and CASP1-catalyzed IL1B and IL18 maturation and secretion in the extracellular milieu. Activation of NLRP1 inflammasome is also required for HMGB1 secretion. The active cytokines and HMGB1 stimulate inflammatory responses. Inflammasomes can also induce pyroptosis, an inflammatory form of programmed cell death (PubMed:22665479, PubMed:17418785). May be activated by muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan, in a NOD2-dependent manner (PubMed:18511561). Contrary to its mouse ortholog, not activated by Bacillus anthracis lethal toxin (PubMed:19651869). It is unclear whether isoform 2 is involved in inflammasome formation. It is not cleaved within the FIIND domain, does not assemble into specks, nor promote IL1B release (PubMed:22665479). However, in an vitro cell-free system, it has been shown to be activated by MDP (PubMed:17349957). Binds ATP (PubMed:11113115, PubMed:15212762). {ECO:0000250|UniProtKB:A1Z198, ECO:0000269|PubMed:11113115, ECO:0000269|PubMed:15212762, ECO:0000269|PubMed:17349957, ECO:0000269|PubMed:17418785, ECO:0000269|PubMed:18511561, ECO:0000269|PubMed:19651869, ECO:0000269|PubMed:22665479, ECO:0000269|PubMed:27662089}.;
- Disease
- DISEASE: Vitiligo-associated multiple autoimmune disease 1 (VAMAS1) [MIM:606579]: A disorder characterized by the association of vitiligo with several autoimmune and autoinflammatory diseases including autoimmune thyroid disease, rheumatoid arthritis and systemic lupus erythematosus. {ECO:0000269|PubMed:17377159}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Palmoplantar carcinoma, multiple self-healing (MSPC) [MIM:615225]: An autosomal dominant disease characterized by keratopathy with neovascularization, bilateral corneal opacification, palmoplantar hyperkeratosis, dyshidrosis, dystrophic nails, and recurrent keratoacanthomas in palmoplantar skin as well as in conjunctival and corneal epithelia. In addition, patients experience a high susceptibility to malignant squamous cell carcinoma. {ECO:0000269|PubMed:23349227, ECO:0000269|PubMed:27662089}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Autoinflammation with arthritis and dyskeratosis (AIADK) [MIM:617388]: A disorder characterized by recurrent fever, diffuse skin dyskeratosis, autoinflammation, autoimmunity, arthritis and high transitional B-cell level. Inheritance can be autosomal dominant or autosomal recessive. {ECO:0000269|PubMed:27965258}. Note=The disease may be caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.926
- RVIS EVS
- 2.71
- RVIS percentile EVS
- 98.94
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.539
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |