NLRP1

Summary

NLRP1 (NLR family pyrin domain containing 1, HGNC:14374) is a protein-coding gene on chromosome 17p13, encoding NACHT, LRR and PYD domains-containing protein 1 (Q9C000). Acts as the sensor component of the NLRP1 inflammasome, which mediates inflammasome activation in response to various pathogen-associated signals, leading to subsequent pyroptosis.

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.

Source: NCBI Gene 22861 — RefSeq curated summary.

At a glance

• Gene–disease (curated): corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 1,245 total — 4 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 46
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_033004

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14374
Approved symbol	NLRP1
Name	NLR family pyrin domain containing 1
Location	17p13
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0926, DKFZp586O1822, CARD7, NAC, CLR17.1, DEFCAP, VAMAS1
Ensembl gene	ENSG00000091592
Ensembl biotype	protein_coding
OMIM	606636
Entrez	22861

Gene structure

Transcript identifiers

Ensembl transcripts: 70 — 31 nonsense_mediated_decay, 26 protein_coding, 11 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000262467, ENST00000269280, ENST00000354411, ENST00000544378, ENST00000571307, ENST00000571451, ENST00000572143, ENST00000572272, ENST00000574406, ENST00000574512, ENST00000576905, ENST00000577119, ENST00000617618, ENST00000699586, ENST00000699612, ENST00000699613, ENST00000699614, ENST00000699615, ENST00000699616, ENST00000699617, ENST00000699618, ENST00000699622, ENST00000699623, ENST00000699624, ENST00000699625, ENST00000699626, ENST00000699629, ENST00000699630, ENST00000699631, ENST00000699632, ENST00000699633, ENST00000699634, ENST00000699635, ENST00000699636, ENST00000699637, ENST00000699638, ENST00000699639, ENST00000699642, ENST00000699643, ENST00000699644, ENST00000699645, ENST00000699646, ENST00000699665, ENST00000699705, ENST00000699706, ENST00000699707, ENST00000699708, ENST00000699709, ENST00000699710, ENST00000699711, ENST00000699712, ENST00000699713, ENST00000699771, ENST00000699772, ENST00000699773, ENST00000699774, ENST00000699775, ENST00000699776, ENST00000699777, ENST00000699800, ENST00000699801, ENST00000699802, ENST00000699803, ENST00000699804, ENST00000699805, ENST00000699806, ENST00000699807, ENST00000699808, ENST00000699809, ENST00000699810

RefSeq mRNA: 5 — MANE Select: NM_033004 NM_001033053, NM_014922, NM_033004, NM_033006, NM_033007

CCDS: CCDS32537, CCDS42244, CCDS42245, CCDS42246, CCDS58508

Canonical transcript exons

ENST00000572272 — 17 exons

Exon	Start	End
ENSE00002274409	5583687	5584509
ENSE00002341965	5520881	5521012
ENSE00003463918	5533897	5533988
ENSE00003503375	5530481	5530704
ENSE00003515691	5581859	5582062
ENSE00003527411	5536851	5536940
ENSE00003536289	5582670	5582846
ENSE00003572357	5558339	5560043
ENSE00003583840	5541857	5542027
ENSE00003603652	5539415	5539585
ENSE00003639525	5517746	5517887
ENSE00003678784	5553386	5553556
ENSE00003680557	5521524	5521786
ENSE00003802704	5532822	5532984
ENSE00003977100	5515473	5515517
ENSE00003977377	5533304	5533384
ENSE00003977655	5514118	5515073

Expression profiles

Bgee: expression breadth ubiquitous, 203 present calls, max score 97.88.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.9728 / max 858.8445, expressed in 1466 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
164044	23.4618	1316
164045	3.1261	191
164041	0.1880	89
164042	0.1242	56
164043	0.0727	28

Top tissues by expression

289 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	97.88	gold quality
monocyte	CL:0000576	94.89	gold quality
mononuclear cell	CL:0000842	94.73	gold quality
leukocyte	CL:0000738	94.60	gold quality
blood	UBERON:0000178	93.46	gold quality
skin of abdomen	UBERON:0001416	93.31	gold quality
spleen	UBERON:0002106	92.58	gold quality
skin of leg	UBERON:0001511	92.48	gold quality
lymph node	UBERON:0000029	90.59	gold quality
right lung	UBERON:0002167	89.82	gold quality
zone of skin	UBERON:0000014	89.65	gold quality
vermiform appendix	UBERON:0001154	89.28	gold quality
omental fat pad	UBERON:0010414	89.14	gold quality
peritoneum	UBERON:0002358	89.08	gold quality
apex of heart	UBERON:0002098	88.76	gold quality
ectocervix	UBERON:0012249	88.60	gold quality
adipose tissue of abdominal region	UBERON:0007808	88.43	gold quality
bone marrow cell	CL:0002092	88.33	gold quality
vagina	UBERON:0000996	87.79	gold quality
descending thoracic aorta	UBERON:0002345	87.73	gold quality
ascending aorta	UBERON:0001496	87.62	gold quality
upper lobe of left lung	UBERON:0008952	87.53	gold quality
thoracic aorta	UBERON:0001515	87.50	gold quality
subcutaneous adipose tissue	UBERON:0002190	87.36	gold quality
caecum	UBERON:0001153	87.09	gold quality
small intestine Peyer’s patch	UBERON:0003454	86.96	gold quality
right lobe of thyroid gland	UBERON:0001119	86.87	gold quality
left lobe of thyroid gland	UBERON:0001120	86.86	gold quality
endocervix	UBERON:0000458	86.63	gold quality
upper lobe of lung	UBERON:0008948	86.33	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, SP1, TP53

miRNA regulators (miRDB)

21 targeting NLRP1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-885-5P	99.59	68.59	879
HSA-MIR-486-5P	99.51	70.39	707
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-5571-5P	99.49	66.99	1764
HSA-MIR-365A-3P	99.43	70.02	836
HSA-MIR-365B-3P	99.43	70.02	836
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-3678-3P	99.31	67.10	1432
HSA-MIR-4738-3P	98.98	67.98	1846
HSA-MIR-4490	98.51	68.47	943
HSA-MIR-4717-5P	98.19	67.97	894
HSA-MIR-4786-5P	97.45	67.89	924
HSA-MIR-2467-5P	97.36	67.71	991
HSA-MIR-7161-3P	96.79	68.79	798
HSA-MIR-6822-3P	96.60	66.06	680
HSA-MIR-1178-5P	95.83	64.12	504
HSA-MIR-3622B-5P	94.62	64.58	835
HSA-MIR-769-5P	94.45	64.56	603

Literature-anchored findings (GeneRIF, showing 40)

• inflammasome comprises caspase-1, caspase-5, Pycard/Asc, and NALP1; a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta (PMID:12191486)
• Related to susceptiblity to vitiligo and autoimmune diseases. (PMID:14691733)
• Over-expression of NALP1 stimulated cell death in both HeLa cells and cerebellar granule neurons. (PMID:15212762)
• NALP 1 and 3 show distinct but separate expression profiles in human tissues suggesting a site-specific role in the inflammatory response (PMID:17164409)
• DNA sequence variants in the NALP1 region are associated with the risk of several epidemiologically associated autoimmune and autoinflammatory diseases, implicating the innate immune system in the pathogenesis of these disorders. (PMID:17377159)
• Antiapoptotic proteins Bcl-2 and Bcl-X(L) bind and suppress NALP1, reducing caspase-1 activation and interleukin-1beta (IL-1beta) production. (PMID:17418785)
• NALP1 genetic variations are involved in predisposition to generalized vitiligo. (PMID:17637824)
• Relative copy numbers for the inflammasome mRNAs for ASC, caspase-1, NALP1, and Pypaf-7 were significantly lower in patients with septic shock compared with critically ill control subjects. (PMID:18263805)
• The pyrin domain of the ASC and NALP1 proteins were simulated at two different pH values, 3.7 and 6.5, with two different force-field parameter sets, and the molecular dynamics simulation trajectories were compared to NMR experimental data (PMID:18348116)
• NALP1 and the innate immune system may be implicated in the pathogenesis of many autoimmune disorders, particularly organ-specific autoimmune diseases. (PMID:18946481)
• significant KPNA1-, NLRP1- and NLRP3-gene expression phenotypes associated with human genotypes of Crohn’s disease, Huntington’s disease and rheumatoid arthritis (PMID:19001869)
• Genetic variations are associated with autoinflammatory disorders and increased susceptibility to microbial infection (PMID:19120479)
• gene polymorphism is associated with vitiligo (PMID:19223160)
• three-way interaction effects of chromosome 7 SNP rs6960920, chromosome 9 SNP rs4744411, and NLRP1 SNP rs6502867 on vitiligo phenotype and autoimmune disease phenotype; effects of both chromosome 7 and NLRP1 SNP rs6502867 on the vitiligo phenotype (PMID:19727120)
• study confirms an association between the coding polymorphism in NLRP1 and Autoimmune Addison’s disease (PMID:20152874)
• study found that 2 SNPs in the NALP1 extended promoter region, rs1008588 and rs2670660 were significantly associated with generalized vitiligo in Arab vitiligo patients; several other SNPs in the NALP1 region were at the margin of significant association (PMID:20574744)
• These findings suggest that the NALP1 inflammasome is critical for mediating innate immune responses to T. gondii infection and pathogenesis. (PMID:21098108)
• results establish NLRP1 as a new genetic susceptibility factor for systemic sclerosis-related pulmonary fibrosis and anti-topoisomerase-positive SSc phenotypes and provides new insights into the pathogenesis of SSc. (PMID:21149496)
• NALP1/NLRP1 inflammasomes may have a role in CD pathogenesis. (PMID:21245836)
• study found KSHV Orf63 is a viral homolog of NLRP1; Orf63 blocked NLRP1-dependent innate immune responses; during the course of evolution with its human host, KSHV has usurped and modified a cellular NLR gene to inhibit the host inflammasome response (PMID:21252346)
• None of the six SNPs in the NLRP1 region were significantly associated with disease susceptibility or the ocular, neurological, and dermatological manifestations of VKH. (PMID:21331694)
• No evidence for association of the polymorphisms in NLRP1 gene with type 1 diabetes in Poland (PMID:21376416)
• These findings provide evidence of an association between single nucleotide variations in the NLRP1 gene and Alzheimer disease (PMID:21946017)
• NLRP1 is associated with rheumatoid arthritis in Han Chinese. (PMID:21976003)
• results identify a function for the FIIND and show that CARD8 and NLRP1 are ZU5-UPA domain-containing autoproteolytic proteins, thus suggesting a novel mechanism for regulating innate immune responses (PMID:22087307)
• Polymorphisms in the innate immunity gene NLRP1 are implicated in some familial forms of vitiligo. Review. (PMID:22117610)
• Twelve single nucleotide polymorphisms within NLRP1, NLRP3, NLRC4, CARD8, CASP1, and IL1B genes were analyzed in 150 HIV-1-infected Brazilian subjects. 2 polymorphisms in NLRP3 and IL1B were significantly associated to the HIV-1 infection. (PMID:22227487)
• results demonstrated that NLRP1 rs2670660 SNP and the NLRP1 rs12150220-rs2670660 A-G haplotype were associated with systemic lupus erythematosus in our study population, and in particular with the development of nephritis, rash and arthritis (PMID:22235789)
• A haplotype, T-T-C-G-A-C, in the NLRP1 gene was associated with a higher risk for Kawasaki disease development. (PMID:22507623)
• NLRP3/NLRP1 polymorphisms are associated with melanoma susceptibility (PMID:22524199)
• Autolytic proteolysis within the function to find domain (FIIND) is required for NLRP1 inflammasome activity. (PMID:22665479)
• we performed a genetic association study in patients with pneumococcal meningitis and found that single-nucleotide polymorphisms in the inflammasome genes CARD8 and NLRP1 are associated with poor disease outcome. (PMID:23053059)
• NLRP1 shows a genetic association with giant cell arteritis. (PMID:23253924)
• We describe a new corneal intraepithelial dyskeratosis and how we identified its causative gene - NLRP1 (PMID:23349227)
• study found that NLRP1 rs12150220 T allele and NLRP1 rs2670660 G allele were significantly associated with autoimmune thyroid disorders compared with controls; NLRP1 may be involved in the pathogenesis of autoimmune thyroid disorders (PMID:23374100)
• Our results do not support the role of the NLRP1 rs8182352 in systemic sclerosis. (PMID:23380025)
• NLRP1 RNA and protein levels were not altered by the predominant high-risk haplotype, indicating that altered function of the corresponding multivariant NLRP1 polypeptide predisposes to autoimmune diseases by activation of the NLRP1 inflammasome (PMID:23382179)
• The charge surface of the NLRP1 CARD structure and a procaspase-1 CARD model suggests potential mechanisms for their association through electrostatic attraction. (PMID:23508996)
• Genetic variation in the inflammasome affects atopic dermatitis susceptibility. (PMID:23563199)
• Studied NLRP1 haplotypes associated with leprosy in Brazilian patients. (PMID:23770116)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Nlrp1a	ENSMUSG00000069830
mus_musculus	Nlrp1b	ENSMUSG00000070390
rattus_norvegicus	Nlrp1a	ENSRNOG00000023143
rattus_norvegicus	Nlrp1b	ENSRNOG00000048125

Paralogs (20): NLRP2 (ENSG00000022556), NOD1 (ENSG00000106100), NLRC5 (ENSG00000140853), NLRP12 (ENSG00000142405), NLRP14 (ENSG00000158077), NLRP4 (ENSG00000160505), NLRX1 (ENSG00000160703), NLRP3 (ENSG00000162711), NOD2 (ENSG00000167207), NLRP7 (ENSG00000167634), NLRC3 (ENSG00000167984), NLRP5 (ENSG00000171487), NLRP13 (ENSG00000173572), NLRP6 (ENSG00000174885), CIITA (ENSG00000179583), NLRP8 (ENSG00000179709), NLRP11 (ENSG00000179873), NLRP10 (ENSG00000182261), NLRP9 (ENSG00000185792), PYDC2 (ENSG00000253548)

Protein

Protein identifiers

NACHT, LRR and PYD domains-containing protein 1 — Q9C000 (reviewed: Q9C000)

Alternative names: Caspase recruitment domain-containing protein 7, Death effector filament-forming ced-4-like apoptosis protein, Nucleotide-binding domain and caspase recruitment domain

All UniProt accessions (44): Q9C000, A0A8V8TNG2, A0A8V8TNH7, A0A8V8TNJ2, A0A8V8TNK6, A0A8V8TNN3, A0A8V8TNP3, A0A8V8TNP9, A0A8V8TNR1, A0A8V8TNR8, A0A8V8TNS2, A0A8V8TNS7, A0A8V8TNU7, A0A8V8TNV1, A0A8V8TNV2, A0A8V8TNV8, A0A8V8TP02, A0A8V8TP05, A0A8V8TP07, A0A8V8TP12, A0A8V8TP14, A0A8V8TP36, A0A8V8TP42, A0A8V8TP48, A0A8V8TP94, A0A8V8TPB4, A0A8V8TPB9, A0A8V8TPC6, A0A8V8TPW2, A0A8V8TQ11, A0A8V8TQ17, A0A8V8TQ55, A0A8V8TQ79, A0A8V8TQ83, A0A8V8TQ85, A0A8V8TQ99, A0A8V8TQA8, A0A8V8TQB3, A0A8V8TQB8, A0A8V8TQE6, A0A8V8TQI5, A0A8V8TQK4, A0A8V8TQL0, I3L0S2

UniProt curated annotations — full annotation on UniProt →

Function. Acts as the sensor component of the NLRP1 inflammasome, which mediates inflammasome activation in response to various pathogen-associated signals, leading to subsequent pyroptosis. Inflammasomes are supramolecular complexes that assemble in the cytosol in response to pathogens and other damage-associated signals and play critical roles in innate immunity and inflammation. Acts as a recognition receptor (PRR): recognizes specific pathogens and other damage-associated signals, such as cleavage by some human enteroviruses and rhinoviruses, double-stranded RNA, UV-B irradiation, or Val-boroPro inhibitor, and mediates the formation of the inflammasome polymeric complex composed of NLRP1, CASP1 and PYCARD/ASC. In response to pathogen-associated signals, the N-terminal part of NLRP1 is degraded by the proteasome, releasing the cleaved C-terminal part of the protein (NACHT, LRR and PYD domains-containing protein 1, C-terminus), which polymerizes and associates with PYCARD/ASC to initiate the formation of the inflammasome complex: the NLRP1 inflammasome recruits pro-caspase-1 (proCASP1) and promotes caspase-1 (CASP1) activation, which subsequently cleaves and activates inflammatory cytokines IL1B and IL18 and gasdermin-D (GSDMD), leading to pyroptosis. In the absence of GSDMD expression, the NLRP1 inflammasome is able to recruit and activate CASP8, leading to activation of gasdermin-E (GSDME). Activation of NLRP1 inflammasome is also required for HMGB1 secretion; the active cytokines and HMGB1 stimulate inflammatory responses. Binds ATP and shows ATPase activity. Plays an important role in antiviral immunity and inflammation in the human airway epithelium. Specifically recognizes a number of pathogen-associated signals: upon infection by human rhinoviruses 14 and 16 (HRV-14 and HRV-16), NLRP1 is cleaved and activated which triggers NLRP1-dependent inflammasome activation and IL18 secretion. Positive-strand RNA viruses, such as Semliki forest virus and long dsRNA activate the NLRP1 inflammasome, triggering IL1B release in a NLRP1-dependent fashion. Acts as a direct sensor for long dsRNA and thus RNA virus infection. May also be activated by muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan, in a NOD2-dependent manner. The NLRP1 inflammasome is also activated in response to UV-B irradiation causing ribosome collisions: ribosome collisions cause phosphorylation and activation of NLRP1 in a MAP3K20-dependent manner, leading to pyroptosis. Constitutes the precursor of the NLRP1 inflammasome, which mediates autoproteolytic processing within the FIIND domain to generate the N-terminal and C-terminal parts, which are associated non-covalently in absence of pathogens and other damage-associated signals. Regulatory part that prevents formation of the NLRP1 inflammasome: in absence of pathogens and other damage-associated signals, interacts with the C-terminal part of NLRP1 (NACHT, LRR and PYD domains-containing protein 1, C-terminus), preventing activation of the NLRP1 inflammasome. In response to pathogen-associated signals, this part is ubiquitinated and degraded by the proteasome, releasing the cleaved C-terminal part of the protein, which polymerizes and forms the NLRP1 inflammasome. Constitutes the active part of the NLRP1 inflammasome. In absence of pathogens and other damage-associated signals, interacts with the N-terminal part of NLRP1 (NACHT, LRR and PYD domains-containing protein 1, N-terminus), preventing activation of the NLRP1 inflammasome. In response to pathogen-associated signals, the N-terminal part of NLRP1 is degraded by the proteasome, releasing this form, which polymerizes and associates with PYCARD/ASC to form of the NLRP1 inflammasome complex: the NLRP1 inflammasome complex then directly recruits pro-caspase-1 (proCASP1) and promotes caspase-1 (CASP1) activation, leading to gasdermin-D (GSDMD) cleavage and subsequent pyroptosis. It is unclear whether is involved in inflammasome formation. It is not cleaved within the FIIND domain, does not assemble into specks, nor promote IL1B release. However, in an vitro cell-free system, it has been shown to be activated by MDP.

Subunit / interactions. Interacts (via LRR repeats) with BCL2 and BCL2L1 (via the loop between motifs BH4 and BH3); these interactions reduce NLRP1 inflammasome-induced CASP1 activation and IL1B release, possibly by impairing NLRP1 interaction with PYCARD. Interacts with NOD2; this interaction is enhanced in the presence of muramyl dipeptide (MDP) and increases IL1B release. Interacts with EIF2AK2/PKR; this interaction requires EIF2AK2 activity, is accompanied by EIF2AK2 autophosphorylation and promotes inflammasome assembly in response to danger-associated signals. Interacts with MEFV; this interaction targets NLRP1 to degradation by autophagy, hence preventing excessive IL1B- and IL18-mediated inflammation. Binds (via LRR domain) to dsDNA and dsRNA. Interacts with DPP9; leading to inhibit activation of the inflammasome. DPP9 acts via formation of a ternary complex, composed of a DPP9 homodimer, one full-length NLRP1 protein, and one cleaved C-terminus of NLRP1 (NACHT, LRR and PYD domains-containing protein 1, C-terminus). Interacts with DPP8; leading to inhibit activation of the inflammasome, probably via formation of a ternary complex with DPP8. Interacts with the C-terminal part of NLRP1 (NACHT, LRR and PYD domains-containing protein 1, C-terminus) in absence of pathogens and other damage-associated signals. Interacts with the N-terminal part of NLRP1 (NACHT, LRR and PYD domains-containing protein 1, N-terminus) in absence of pathogens and other damage-associated signals. Homomultimer; forms the NLRP1 inflammasome polymeric complex, a filament composed of homopolymers of this form in response to pathogens and other damage-associated signals. The NLRP1 inflammasome polymeric complex associates with PYCARD/ASC. Interacts (via CARD domain) with PYCARD/ASC (via CARD domain); leading to pro-caspase-1 (proCASP1) recruitment. Pro-caspase-1 (proCASP1) filament formation increases local enzyme concentration, resulting in trans-autocleavage and activation. Active CASP1 then processes IL1B and IL18 precursors, leading to the release of mature cytokines in the extracellular milieu and inflammatory response. (Microbial infection) Interacts with vaccinia virus protein F1. (Microbial infection) Interacts with human herpes virus 8/HHV-8 proteins ORF45; relieving autoinhibition of the NLRP1 inflammasome.

Subcellular location. Cytoplasm. Cytosol. Nucleus Inflammasome Nucleus.

Tissue specificity. Widely expressed. Abundantly expressed in primary immune cells (isoform 1 and isoform 2), including in neutrophils, monocytes/macrophages, dendritic cells (mostly Langerhans cells), and B- and T-lymphocytes (at protein level). Strongly expressed in epithelial cells lining the glandular epithelium, such as that of the gastrointestinal tract (stomach, small intestine, colon), the respiratory tract (trachea and bronchi), and the endometrial and endocervical glands, gallbladder, prostate, and breast (at protein level). In testis, expressed in spermatogonia and primary spermatocytes, but not in Sertoli cells (at protein level). In the brain, expressed in neurons, in particular in pyramidal ones and in oligodendrocytes, but not detected in microglia (at protein level). Expressed in adult and fetal ocular tissues, including in adult and 24-week old fetal choroid, sclera, cornea, and optic nerve, as well as in adult retina and fetal retina/retinal pigment epithelium. Highly expressed in the skin throughout the epidermis and in dermal fibroblasts, in both glabrous skin and plantar skin. It is detected in keratinocytes, but not in melanocytes. Expressed in epidermal appendages such as hair follicles.

Post-translational modifications. Autocatalytically cleaved. Autocatalytic cleavage in FIIND region occurs constitutively, prior to activation signals, and is required for inflammasome activity (IL1B release), possibly by facilitating CASP1 binding. Both N- and C-terminal parts remain associated non-covalently. Ubiquitinated by the cullin:ZER1/ZYG11B complex in response to pathogen-associated signals, leading to its degradation by the proteasome and subsequent release of the cleaved C-terminal part of the protein (NACHT, LRR and PYD domains-containing protein 1, C-terminus), which polymerizes and forms the NLRP1 inflammasome. Phosphorylated by MAP3K20 isoform ZAKalpha, MAPK11 and MAPK14 in response to UV-B irradiation and ribosome collisions, promoting activation of the NLRP1 inflammasome and pyroptosis. (Microbial infection) Cleaved between Gln-130 and Gly-131 by the Protease 3C from various human enteroviruses and rhinoviruses (EV68, EV71, Coxsackievirus B3, HRV-14 and HRV-16). This cleavage triggers N-glycine-mediated proteasomal degradation of the autoinhibitory NLRP1 N-terminal fragment via the cullin:ZER1/ZYG11B complex which liberates the activating C-terminal fragment and activates NLRP1 inflammasome. (Microbial infection) Cleaved between Gln-333 and Gly-334 by the 3C-like proteinase nsp5 from human coronavirus SARS-CoV-2. This cleavage liberates the activating C-terminal fragment and activates NLRP1 inflammasome, leading to downstream activation of GSDME and lung epithelial cell death.

Disease relevance. 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. Disease susceptibility is associated with variants affecting the gene represented in this entry. 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. The disease is caused by variants affecting the gene represented in this entry. 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. The disease may be caused by variants affecting the gene represented in this entry. Respiratory papillomatosis, juvenile recurrent, congenital (JRRP) [MIM:618803] An autosomal recessive disease characterized by recurrent growth of papillomas in the respiratory tract, and onset in early childhood. Papillomas are most commonly found in the larynx but may occur anywhere from the mouth to the bronchi. Children typically present within the first years of life with hoarseness or, in more severe cases, respiratory distress or stridor and airway obstruction. JRRP is associated with infection of the upper airway by human papillomaviruses of the alpha genus. The infection is thought to occur by vertical transmission at birth. The disease may be caused by variants affecting the gene represented in this entry.

Activity regulation. NLRP1 inflammasome is activated by cleavage by the Protease 3C from various human enteroviruses and rhinoviruses (EV68, EV71, Coxsackievirus B3, HRV-14 and HRV-16): cleavage promotes ubiquitination and degradation of the N-terminal part, releasing the cleaved C-terminal part of the protein (NACHT, LRR and PYD domains-containing protein 1, C-terminus), which polymerizes and forms the NLRP1 inflammasome. Activated double-stranded RNA: positive-strand RNA viruses such as Semliki forest virus and long dsRNA activate the NLRP1 inflammasome. In contrast to its mouse ortholog, not activated by Bacillus anthracis lethal toxin. NLRP1 inflammasome is inhibited by DPP8 and DPP9, which sequester the C-terminal fragment of NLRP1 (NACHT, LRR and PYD domains-containing protein 1, C-terminus) in a ternary complex, thereby preventing NLRP1 oligomerization and activation. NLRP1 inflammasome is activated by Val-boroPro (Talabostat, PT-100), an inhibitor of dipeptidyl peptidases DPP8 and DPP9. Val-boroPro relieves inhibition of DPP8 and/or DPP9 by promoting disruption of the ternary complex, releasing its C-terminal part from autoinhibition. ATPase activity is activated by dsRNA-binding but not dsDNA-binding. (Microbial infection) The NLRP1 inflammasome is activated by human herpes virus 8/HHV-8 protein ORF45, which interacts with the N-terminal part of NLRP1 and promotes its translocation into the nucleus, relieving autoinhibition and leading to activation. (Microbial infection) NLRP1 inflammasome is activated by cleavage by the 3C-like proteinase nsp5 from human coronavirus SARS-CoV-2.

Domain organisation. The CARD domain, rather than the pyrin domain, is involved in the interaction with PYCARD, CASP1 and CASP5. The ZAKalpha motifs are recognized and phosphorylated by isoform ZAKalpha of MAP3K20. The leucine-rich repeat (LRR) domain may be involved in autoinhibition in the absence of activating signal, possibly through intramolecular interaction with the NACHT domain. Serves as the predominant binding domain for dsRNA and dsDNA. The FIIND (domain with function to find) region is involved in homomerization, but not in CASP1-binding. Autocatalytic cleavage in this region occurs constitutively, prior to activation signals, and is required for inflammasome activity (IL1B release), possibly by facilitating CASP1 binding. Both N- and C-terminal fragments remain associated. The pyrin domain mediates an autoinhibitory function, potentially acting as a threshold modulator, which allows NLRP1 to discriminate long from short dsRNA. Inhibits ATPase activity of the NATCH domain. The C-terminal part of NLRP1 oligomerizes to form the core of the NLRP1 inflammasome filament: in the filament, the CARD domains form a central helical filaments that are promoted by oligomerized, but flexibly linked, UPA regions surrounding the filaments. The UPA region reduces the threshold needed for filament formation and signaling. Must recruit the adapter PYCARD/ASC to facilitate CASP1 interaction and polymerization. Upon dsRNA-binding via its LRR domain, NACHT domain gains ATPase activity which is inhibited by the pyrin domain.

Induction. Up-regulated by ATF4 during endoplasmic reticulum (ER) stress response. Up-regulated in arterial endothelial cells exposed to plasma from patients with peripheral arterial disease, but not to plasma from healthy controls.

Miscellaneous. In macrophages and dendritic cells, NLRP1 inflammasome activation of CASP1 and IL1B maturation can be dampened by direct contact with activated effector and memory T-cells. This effect may be mediated by hexameric TNF ligands, such as CD40LG.

Similarity. Belongs to the NLRP family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9C000-1	1, NAC beta, DEFCAP-L, NALP1-L	yes
Q9C000-2	2, NAC alpha, DEFCAP-S, NALP1-S, NLRP1deltaEx14
Q9C000-3	3, NAC gamma
Q9C000-4	4, NAC delta
Q9C000-5	5

RefSeq proteins (5): NP_001028225, NP_055737, NP_127497, NP_127499, NP_127500 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001315	CARD	Domain
IPR001611	Leu-rich_rpt	Repeat
IPR004020	DAPIN	Domain
IPR007111	NACHT_NTPase	Domain
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR025307	FIIND_dom	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR033516	CARD8/ASC/NALP1_CARD	Domain
IPR041075	NOD1/2_WH	Domain
IPR041267	NLRP_HD2	Domain
IPR051249	NLRP_Inflammasome	Family

Pfam: PF00560, PF00619, PF02758, PF05729, PF13516, PF13553, PF17776, PF17779, PF23679

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (248 total): mutagenesis site 69, strand 55, helix 46, sequence variant 17, modified residue 16, turn 11, repeat 6, region of interest 5, splice variant 5, domain 4, chain 3, sequence conflict 3, site 3, short sequence motif 2, compositionally biased region 2, binding site 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
4IM6	X-RAY DIFFRACTION	1.65
4IFP	X-RAY DIFFRACTION	1.99
8ZGD	X-RAY DIFFRACTION	2.05
5Y3S	X-RAY DIFFRACTION	2.45
6X6C	ELECTRON MICROSCOPY	2.9
3KAT	X-RAY DIFFRACTION	3.1
7WGE	ELECTRON MICROSCOPY	3.4
6X6A	ELECTRON MICROSCOPY	3.6
6K7V	ELECTRON MICROSCOPY	3.7
6XKK	ELECTRON MICROSCOPY	3.72
9BJ9	ELECTRON MICROSCOPY	4.2
1PN5	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9C000-F1	68.81	0.18

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3): 130–131 ((microbial infection) cleavage; by human rhinovirus 14 (hrv-14) protease 3c); 333–334 ((microbial infection) cleavage; by coronavirus sars-cov-2 proteinase nsp5); 1212–1213 (cleavage; by autolysis)

Ligand- & substrate-binding residues (1): 334–341

Post-translational modifications (16): 93, 99, 101, 107, 112, 113, 114, 129, 132, 163, 168, 170, 173, 178, 179, 180

Mutagenesis-validated functional residues (69):

Position	Phenotype
1387	does not affect formation of an inflammasome filament together with pycard/asc.
1388	does not affect formation of an inflammasome filament together with pycard/asc.
1392	abolished formation of an inflammasome filament together with pycard/asc.
1392	impaired ability to induce programmed cell death.
1395	abolished formation of an inflammasome filament together with pycard/asc.
1397	impaired ability to induce programmed cell death. abolished formation of an inflammasome filament together with pycard/a
1401	impaired ability to induce programmed cell death.
1402	abolished formation of an inflammasome filament together with pycard/asc.
1404	abolished formation of an inflammasome filament together with pycard/asc.
1406	does not affect formation of an inflammasome filament together with pycard/asc.
1410	abolished formation of an inflammasome filament together with pycard/asc.
1411	impaired ability to induce programmed cell death. abolished formation of an inflammasome filament together with pycard/a
1413	abolished formation of an inflammasome filament together with pycard/asc.
1414	impaired ability to induce programmed cell death. abolished formation of an inflammasome filament together with pycard/a
1415	abolished formation of an inflammasome filament together with pycard/asc.
1420	abolished formation of an inflammasome filament together with pycard/asc.
1422	abolished formation of an inflammasome filament together with pycard/asc.
1427	abolished formation of an inflammasome filament together with pycard/asc.
1427	impaired ability to induce programmed cell death.
1428	does not affect formation of an inflammasome filament together with pycard/asc.
1434	does not affect formation of an inflammasome filament together with pycard/asc.
1437	abolished formation of an inflammasome filament together with pycard/asc.
1445	abolished inflammasome filament formation. impaired ability to induce programmed cell death, but retains caps1 processin
1449	does not affect formation of an inflammasome filament together with pycard/asc.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-844455	The NLRP1 inflammasome

MSigDB gene sets: 365 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, WALLACE_PROSTATE_CANCER_RACE_UP, REACTOME_INNATE_IMMUNE_SYSTEM, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_CELLULAR_RESPONSE_TO_UV, GOBP_INFLAMMATORY_RESPONSE, REACTOME_INFLAMMASOMES, REACTOME_NUCLEOTIDE_BINDING_DOMAIN_LEUCINE_RICH_REPEAT_CONTAINING_RECEPTOR_NLR_SIGNALING_PATHWAYS, PEREZ_TP63_TARGETS, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, ADDYA_ERYTHROID_DIFFERENTIATION_BY_HEMIN

GO Biological Process (28): activation of innate immune response (GO:0002218), pattern recognition receptor signaling pathway (GO:0002221), apoptotic process (GO:0006915), inflammatory response (GO:0006954), signal transduction (GO:0007165), response to muramyl dipeptide (GO:0032495), positive regulation of interleukin-1 beta production (GO:0032731), defense response to bacterium (GO:0042742), regulation of apoptotic process (GO:0042981), regulation of inflammatory response (GO:0050727), positive regulation of inflammatory response (GO:0050729), protein homooligomerization (GO:0051260), neuron apoptotic process (GO:0051402), defense response to virus (GO:0051607), pyroptotic inflammatory response (GO:0070269), cellular response to UV-B (GO:0071493), intrinsic apoptotic signaling pathway (GO:0097193), self proteolysis (GO:0097264), antiviral innate immune response (GO:0140374), NLRP1 inflammasome complex assembly (GO:1904784), immune system process (GO:0002376), proteolysis (GO:0006508), programmed cell death (GO:0012501), innate immune response (GO:0045087), protein maturation (GO:0051604), canonical inflammasome complex assembly (GO:0140632), positive regulation of pyroptotic inflammatory response (GO:0140639), pyroptotic cell death (GO:0141201)

GO Molecular Function (15): double-stranded DNA binding (GO:0003690), double-stranded RNA binding (GO:0003725), ATP binding (GO:0005524), peptidase activity (GO:0008233), cysteine-type endopeptidase activator activity involved in apoptotic process (GO:0008656), ATP hydrolysis activity (GO:0016887), enzyme binding (GO:0019899), protein domain specific binding (GO:0019904), signaling adaptor activity (GO:0035591), pattern recognition receptor activity (GO:0038187), cysteine-type endopeptidase activator activity (GO:0140608), molecular condensate scaffold activity (GO:0140693), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (8): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), NLRP1 inflammasome complex (GO:0072558), NLRP3 inflammasome complex (GO:0072559), canonical inflammasome complex (GO:0061702)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Inflammasomes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
defense response	3
inflammatory response	3
cellular anatomical structure	3
apoptotic signaling pathway	2
apoptotic process	2
protein binding	2
protein-macromolecule adaptor activity	2
nuclear lumen	2
canonical inflammasome complex	2
activation of immune response	1
positive regulation of innate immune response	1
innate immune response-activating signaling pathway	1
programmed cell death	1
execution phase of apoptosis	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
response to nitrogen compound	1
response to oxygen-containing compound	1
interleukin-1 beta production	1
regulation of interleukin-1 beta production	1
positive regulation of interleukin-1 production	1
response to bacterium	1
regulation of programmed cell death	1
regulation of defense response	1
regulation of response to external stimulus	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
regulation of inflammatory response	1
protein complex oligomerization	1
response to virus	1
response to UV-B	1
cellular response to UV	1
intracellular signal transduction	1
proteolysis	1
innate immune response	1
defense response to virus	1
canonical inflammasome complex assembly	1

Protein interactions and networks

STRING

1453 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NLRP1	MEFV	O15553	999
NLRP1	NLRC4	Q9NPP4	999
NLRP1	CASP1	P29466	999
NLRP1	AIM2	O14862	998
NLRP1	CASP5	P51878	998
NLRP1	NLRP6	P59044	987
NLRP1	NLRP3	Q96P20	986
NLRP1	NLRP7	Q8WX94	986
NLRP1	PYCARD	Q9ULZ3	985
NLRP1	NLRP12	P59046	985
NLRP1	NLRP2	Q9NX02	984
NLRP1	BCL2	P10415	982
NLRP1	BCL2L1	Q07817	974
NLRP1	NAIP	Q13075	971
NLRP1	NOD2	Q9HC29	955

IntAct

42 interactions, top by confidence:

A	B	Type	Score
NLRP1	BCL2	psi-mi:“MI:0915”(physical association)	0.750
BCL2	NLRP1	psi-mi:“MI:0915”(physical association)	0.750
NLRP1	BCL2	psi-mi:“MI:0914”(association)	0.750
NLRP1	BCL2	psi-mi:“MI:0403”(colocalization)	0.750
BCL2	NLRP1	psi-mi:“MI:0407”(direct interaction)	0.750
CASP1	NLRP1	psi-mi:“MI:0915”(physical association)	0.660
BCL2L1	NLRP1	psi-mi:“MI:0915”(physical association)	0.650
NLRP1	BCL2L1	psi-mi:“MI:0915”(physical association)	0.650
NLRP1	BCL2L1	psi-mi:“MI:0914”(association)	0.650
NLRP1	PYCARD	psi-mi:“MI:0915”(physical association)	0.560
NLRP1	BCL2L1	psi-mi:“MI:0407”(direct interaction)	0.440
BCL2L1	NLRP1	psi-mi:“MI:0407”(direct interaction)	0.440
NLRP1	CASP5	psi-mi:“MI:0915”(physical association)	0.400
NOD2	NLRP1	psi-mi:“MI:0915”(physical association)	0.400
EIF2AK2	NLRP1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (49): CLTC (Co-fractionation), CSNK1E (Co-fractionation), EIF6 (Co-fractionation), SMC2 (Co-fractionation), NLRP1 (Affinity Capture-MS), NLRP1 (Affinity Capture-RNA), NLRP1 (Affinity Capture-MS), NLRP1 (Affinity Capture-MS), NLRP1 (Affinity Capture-MS), NLRP1 (Affinity Capture-Western), NLRP1 (Proximity Label-MS), NLRP1 (Affinity Capture-Western), NLRP1 (Affinity Capture-Western), NLRP1 (Co-purification), NLRP1 (Affinity Capture-MS)

ESM2 similar proteins: A1Z198, A6QLE5, B0FPE9, D4A523, D9I2F9, D9I2G1, D9I2G3, D9I2G4, D9I2H0, E9Q5G7, E9Q5R7, P59045, P59046, P59047, Q0GKD5, Q288C4, Q2LKU9, Q2LKV2, Q2LKV5, Q2LKW6, Q3TKR3, Q3UWY1, Q63035, Q647I9, Q66X01, Q66X03, Q66X05, Q66X19, Q66X22, Q6B966, Q7RTR0, Q7TPX8, Q86W24, Q86W25, Q86W26, Q86W28, Q8BU40, Q8BVP1, Q8C6J9, Q8CCN1

Diamond homologs: A1Z198, A6QLE5, A8Y3R9, B0FPE9, D4A523, D9I2F9, D9I2G1, D9I2G3, D9I2G4, D9I2H0, E9Q5R7, P10775, P13489, P29315, P59044, P59046, P59047, Q0GKD5, Q2LKU9, Q2LKV2, Q2LKV5, Q2LKW6, Q5RAV7, Q63035, Q6B966, Q86W24, Q86W25, Q86W26, Q8CCN1, Q8HXK9, Q8HZP9, Q8R4B8, Q91VI7, Q91WS2, Q96P20, Q9C000, Q9EPB4, Q9I9N6, Q9ULZ3, Q9Y2G2

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
NLRP1	“form complex”	“NLRP1 inflammasome”	binding
DAMPS	“up-regulates activity”	NLRP1
PAMPs	“up-regulates activity”	NLRP1

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 25 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
defense response to virus	5	15.1×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1245 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	1
Uncertain significance	721
Likely benign	383
Benign	37

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
375413	NM_033004.4(NLRP1):c.160G>A (p.Ala54Thr)	Pathogenic
393318	NM_001033053.2(NLRP1):c.2358-?_2528+?del	Pathogenic
50316	NM_033004.4(NLRP1):c.230T>C (p.Met77Thr)	Pathogenic
827581	NM_033004.4(NLRP1):c.2264C>A (p.Thr755Asn)	Pathogenic
375414	NM_033004.4(NLRP1):c.197C>T (p.Ala66Val)	Likely pathogenic

SpliceAI

3102 predictions. Top by Δscore:

Variant	Effect	Δscore
17:5517781:T:C	donor_gain	1.0000
17:5517886:TCCT:T	acceptor_loss	1.0000
17:5517887:CCTG:C	acceptor_loss	1.0000
17:5517888:C:CC	acceptor_gain	1.0000
17:5517889:T:C	acceptor_loss	1.0000
17:5521573:T:TA	donor_gain	1.0000
17:5532981:TCCT:T	acceptor_gain	1.0000
17:5532982:CCTC:C	acceptor_gain	1.0000
17:5532985:C:CC	acceptor_gain	1.0000
17:5539410:CTTA:C	donor_loss	1.0000
17:5539413:A:AC	donor_gain	1.0000
17:5539413:A:AG	donor_loss	1.0000
17:5539413:AC:A	donor_gain	1.0000
17:5539413:ACC:A	donor_gain	1.0000
17:5539414:C:CC	donor_gain	1.0000
17:5539414:CC:C	donor_gain	1.0000
17:5539414:CCC:C	donor_gain	1.0000
17:5541855:A:AC	donor_gain	1.0000
17:5541856:C:CC	donor_gain	1.0000
17:5541856:CTG:C	donor_gain	1.0000
17:5541870:G:C	donor_gain	1.0000
17:5553380:ACTC:A	donor_loss	1.0000
17:5553382:TCACC:T	donor_loss	1.0000
17:5553384:A:AC	donor_gain	1.0000
17:5553385:C:CC	donor_gain	1.0000
17:5553385:CCG:C	donor_gain	1.0000
17:5582058:GATTT:G	acceptor_gain	1.0000
17:5582060:TTT:T	acceptor_gain	1.0000
17:5582061:TT:T	acceptor_gain	1.0000
17:5582062:TCTGG:T	acceptor_loss	1.0000

AlphaMissense

9586 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:5559613:G:C	F361L	0.984
17:5559613:G:T	F361L	0.984
17:5559615:A:G	F361L	0.984
17:5514853:T:A	K1441N	0.981
17:5514853:T:G	K1441N	0.981
17:5559676:C:A	K340N	0.981
17:5559676:C:G	K340N	0.981
17:5517802:A:G	L1334P	0.980
17:5514833:A:G	L1448P	0.976
17:5514870:A:G	W1436R	0.975
17:5514870:A:T	W1436R	0.975
17:5517767:A:G	W1346R	0.975
17:5517767:A:T	W1346R	0.975
17:5514837:C:G	A1447P	0.974
17:5515010:A:G	L1389P	0.972
17:5521558:A:G	L1250P	0.972
17:5514868:C:A	W1436C	0.970
17:5514868:C:G	W1436C	0.970
17:5559677:T:A	K340M	0.970
17:5520980:A:C	F1272L	0.969
17:5520980:A:T	F1272L	0.969
17:5520982:A:G	F1272L	0.969
17:5583886:G:C	F24L	0.969
17:5583886:G:T	F24L	0.969
17:5583888:A:G	F24L	0.969
17:5514968:A:G	L1403P	0.967
17:5559614:A:G	F361S	0.967
17:5559677:T:G	K340T	0.967
17:5521671:G:C	F1212L	0.966
17:5521671:G:T	F1212L	0.966

dbSNP variants (sampled 300 via entrez): RS1000001642 (17:5555806 A>G), RS1000027860 (17:5561728 C>A,T), RS1000028564 (17:5521451 G>A,C), RS1000050606 (17:5549145 G>A), RS1000071791 (17:5550020 C>A), RS1000092858 (17:5557109 T>C), RS1000156641 (17:5585974 T>G), RS1000181323 (17:5503206 G>C), RS1000213388 (17:5581795 C>T), RS1000316105 (17:5561067 T>A,G), RS1000463136 (17:5561421 A>C,G,T), RS1000471942 (17:5573769 G>T), RS1000493665 (17:5526464 G>C), RS1000551452 (17:5565309 T>A), RS1000616487 (17:5566931 CTT>C)

Disease associations

OMIM: gene MIM:606636 | disease phenotypes: MIM:606579, MIM:615225, MIM:616964, MIM:618803, MIM:617388

GenCC curated gene-disease

Disease	Classification	Inheritance
corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome	Strong	Autosomal dominant
autoinflammation with arthritis and dyskeratosis	Strong	Autosomal recessive

Mondo (5): vitiligo-associated multiple autoimmune disease susceptibility 1 (MONDO:0011684), corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome (MONDO:0014089), respiratory papillomatosis, juvenile recurrent, congenital (MONDO:0032925), autoinflammation with arthritis and dyskeratosis (MONDO:0060457), prostate cancer (MONDO:0008315)

Orphanet (3): OBSOLETE: Vitiligo-associated autoimmune disease (Orphanet:247871), Corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome (Orphanet:352662), Familial prostate cancer (Orphanet:1331)

HPO phenotypes

46 total (30 of 46 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000343	Long philtrum
HP:0000470	Short neck
HP:0000505	Visual impairment
HP:0000554	Uveitis
HP:0000613	Photophobia
HP:0000958	Dry skin
HP:0000968	Ectodermal dysplasia
HP:0000972	Palmoplantar hyperkeratosis
HP:0000982	Palmoplantar keratoderma
HP:0001036	Parakeratosis
HP:0001045	Vitiligo
HP:0001097	Keratoconjunctivitis sicca
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001609	Hoarse voice
HP:0001744	Splenomegaly
HP:0001890	Autoimmune hemolytic anemia
HP:0001954	Recurrent fever
HP:0002240	Hepatomegaly
HP:0002257	Chronic rhinitis
HP:0002860	Squamous cell carcinoma
HP:0003237	Increased circulating IgG concentration
HP:0003261	Increased circulating IgA concentration
HP:0003493	Antinuclear antibody positivity
HP:0003593	Infantile onset
HP:0005764	Polyarticular arthritis
HP:0006094	Finger joint hypermobility
HP:0007502	Follicular hyperkeratosis

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003720_43	Migraine	7.000000e-09

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1741214 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 4,426 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1334033	PERHEXILINE MALEATE	4	1,054
CHEMBL421701	DITHIAZANINE IODIDE	4	3,372

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — NOD-like receptor family

Binding affinities (BindingDB)

27 measured of 36 human assays (41 total across all organisms); most potent 27 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
1-[3-(4-chlorophenyl)-5-[(4-fluorobenzyl)amino]-1,2,4-triazol-1-yl]-2-methoxy-ethanone	IC50	1800 nM
N-(4-acetylphenyl)-N’-(4-chlorophenyl)urea	IC50	2980 nM
SMR000136884	IC50	5330 nM
MLS000552436	IC50	5800 nM
SMR000590891	IC50	6440 nM
MLS000680937	IC50	6510 nM
MLS000696693	IC50	6520 nM
5-[chloranyl-[1-(4-methylphenyl)-1,2,3,4-tetrazol-5-yl]methyl]-1-(4-methylphenyl)-1,2,3,4-tetrazole	IC50	6590 nM
(2Z)-3-ethyl-2-[(2E,4E)-5-(3-ethyl-1,3-benzothiazol-3-ium-2-yl)penta-2,4-dienylidene]-1,3-benzothiazole;iodide	EC50	6670 nM
MLS001181479	IC50	7100 nM
MLS000719868	IC50	10200 nM
cid_2287872	IC50	11500 nM
1-[6-(4-fluoranylphenoxy)hexyl]-4-(2-methoxyphenyl)piperazine	IC50	13200 nM
SMR000272413	IC50	15000 nM
perhexiline maleate	IC50	15900 nM
SMR000296786	IC50	18800 nM
SMR000226857	IC50	19800 nM
cid_2788239	IC50	20600 nM
4-(2,4-dichlorophenoxy)-N-isopropylbutanamide	IC50	35800 nM
3-[(5-methylthiophene-3-carbonyl)amino]thiophene-2-carboxylic acid methyl ester	IC50	38500 nM
N-(4-methylphenyl)-2-[(4-propan-2-yloxyphenyl)amino]ethanamide	IC50	42600 nM
(5Z)-3-[1,1-bis(oxidanylidene)thiolan-3-yl]-5-(pyridin-3-ylmethylidene)-2-sulfanylidene-1,3-thiazolidin-4-one	IC50	49100 nM
2,4-dichloro-N-[4-(1-pyrrolyl)phenyl]benzenesulfonamide	IC50	56800 nM
benzoic acid (5-methyl-2-pyridin-4-yl-4-thiazolyl) ester	IC50	56900 nM
SMR000255355	IC50	61000 nM
4-(benzimidazol-1-yl)-1-methyl-3-nitroquinolin-2-one	IC50	72300 nM
MLS000105423	IC50	87600 nM

ChEMBL bioactivities

5 potent at pChembl≥5 of 29 total, top 5 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.23	IC50	5830	nM	CHEMBL1450616
5.10	IC50	7920	nM	CHEMBL1405204
5.07	IC50	8500	nM	CHEMBL1376392
5.06	IC50	8750	nM	CHEMBL1312788
5.01	IC50	9660	nM	CHEMBL1388040

CTD chemical–gene interactions

61 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, affects methylation, affects cotreatment, decreases expression, increases abundance	4
Air Pollutants	increases expression, affects cotreatment, decreases expression, increases abundance, affects expression	4
Valproic Acid	increases expression, increases methylation, affects expression	4
Benzo(a)pyrene	affects methylation, increases expression	3
Particulate Matter	decreases reaction, increases expression, increases abundance, affects expression	3
Resveratrol	affects cotreatment, increases expression	2
Arsenic	affects cotreatment, decreases expression, increases abundance	2
Cisplatin	affects cotreatment, increases expression, affects expression	2
Ozone	affects cotreatment, decreases expression, increases abundance, affects expression	2
Smoke	decreases expression, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
sotorasib	affects cotreatment, decreases expression	1
dicrotophos	increases expression	1
beauvericin	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
sanguinarine	affects cotreatment, increases expression	1
bisphenol A	decreases methylation	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
arsenite	affects expression	1
cobaltous chloride	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
monomethylarsonous acid	increases expression	1
pinostrobin	increases expression	1
nutlin 3	affects cotreatment, increases expression	1

ChEMBL screening assays

2 unique, capped per target: 1 functional, 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1738356	Functional	PUBCHEM_BIOASSAY: Dose Response confirmation of uHTS for the identification of inhibitors of NALP1 in yeast using a luminescent assay. (Class of assay: confirmatory) [Related pubchem assays (depositor defined):AID2071, AID2092]	PubChem BioAssay data set
CHEMBL5504353	Binding	Inhibition of NLRP1 inflammasome in Val-boroPro-induced human THP-M cells assessed as inhibition of IL-1beta level at 20 to 60 uM pretreated for 24 hrs followed by stimulated with LPS by ELISA	Discovery and Development of NLRP3 Inhibitors Targeting the LRR Domain to Disrupt NLRP3-NEK7 Interaction for the Treatment of Rheumatoid Arthritis. — J Med Chem

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer