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NLRP3 NLR family pyrin domain containing 3 [ Homo sapiens (human) ]

Gene ID: 114548, updated on 20-Jun-2021

Summary

Official Symbol
NLRP3provided by HGNC
Official Full Name
NLR family pyrin domain containing 3provided by HGNC
Primary source
HGNC:HGNC:16400
See related
Ensembl:ENSG00000162711 MIM:606416
Gene type
protein coding
RefSeq status
REVIEWED
Organism
Homo sapiens
Lineage
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as
AII; AVP; FCU; MWS; FCAS; KEFH; CIAS1; FCAS1; NALP3; C1orf7; CLR1.1; DFNA34; PYPAF1; AGTAVPRL
Summary
This gene encodes a pyrin-like protein containing a pyrin domain, a nucleotide-binding site (NBS) domain, and a leucine-rich repeat (LRR) motif. This protein interacts with the apoptosis-associated speck-like protein PYCARD/ASC, which contains a caspase recruitment domain, and is a member of the NLRP3 inflammasome complex. This complex functions as an upstream activator of NF-kappaB signaling, and it plays a role in the regulation of inflammation, the immune response, and apoptosis. The SARS-CoV 3a protein, a transmembrane pore-forming viroporin, has been shown to activate the NLRP3 inflammasome via the formation of ion channels in macrophages. Mutations in this gene are associated with familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, neonatal-onset multisystem inflammatory disease (NOMID), keratoendotheliitis fugax hereditarian, and deafness, autosomal dominant 34, with or without inflammation. Multiple alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. Alternative 5' UTR structures are suggested by available data; however, insufficient evidence is available to determine if all of the represented 5' UTR splice patterns are biologically valid. [provided by RefSeq, Aug 2020]
Annotation information
Note: This gene has been reviewed for its involvement in coronavirus biology, and is involved in cytokine storm inflammatory response.
Expression
Biased expression in bone marrow (RPKM 20.0), appendix (RPKM 6.0) and 9 other tissues See more
Orthologs
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Genomic context

See NLRP3 in Genome Data Viewer
Location:
1q44
Exon count:
11
Annotation release Status Assembly Chr Location
109.20210514 current GRCh38.p13 (GCF_000001405.39) 1 NC_000001.11 (247416163..247448823)
105.20201022 previous assembly GRCh37.p13 (GCF_000001405.25) 1 NC_000001.10 (247579475..247612119)

Chromosome 1 - NC_000001.11Genomic Context describing neighboring genes Neighboring gene LOC107985115 Neighboring gene uncharacterized LOC107985375 Neighboring gene olfactory receptor family 2 subfamily B member 11 Neighboring gene olfactory receptor family 2 subfamily W member 5 pseudogene

Genomic regions, transcripts, and products

Expression

  • Project title: HPA RNA-seq normal tissues
  • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
  • BioProject: PRJEB4337
  • Publication: PMID 24309898
  • Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Phenotypes

Associated conditions

Description Tests
A genome-wide association study for reading and language abilities in two population cohorts.
GeneReviews: Not available
Association of novel genetic Loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts.
GeneReviews: Not available
Chronic infantile neurological, cutaneous and articular syndrome
MedGen: C0409818 OMIM: 607115 GeneReviews: Not available
Compare labs
Deafness, autosomal dominant 34, with or without inflammation
MedGen: C4521680 OMIM: 617772 GeneReviews: Not available
Compare labs
Familial amyloid nephropathy with urticaria AND deafness
MedGen: C0268390 OMIM: 191900 GeneReviews: Not available
Compare labs
Familial cold autoinflammatory syndrome 1
MedGen: C4551895 OMIM: 120100 GeneReviews: Not available
Compare labs
Keratitis fugax hereditaria
MedGen: C1835697 OMIM: 148200 GeneReviews: Not available
Compare labs
Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels.
GeneReviews: Not available
Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease.
GeneReviews: Not available

HIV-1 interactions

Protein interactions

Protein Gene Interaction Pubs
Envelope transmembrane glycoprotein gp41 env HIV-1 inhibitors T20, NVP, AZT, and raltegravir significantly attenuate HIV-1-induced IL-1B production and NLRP3 activation, suggesting that HIV-1 gp41, RT, and IN are required for pro-IL-1B expression and NLRP3 activation PubMed
integrase gag-pol HIV-1 inhibitors T20, NVP, AZT, and raltegravir significantly attenuate HIV-1-induced IL-1B production and NLRP3 activation, suggesting that HIV-1 gp41, RT, and IN are required for pro-IL-1B expression and NLRP3 activation PubMed
reverse transcriptase gag-pol HIV-1 inhibitors T20, NVP, AZT, and raltegravir significantly attenuate HIV-1-induced IL-1B production and NLRP3 activation, suggesting that HIV-1 gp41, RT, and IN are required for pro-IL-1B expression and NLRP3 activation PubMed

Go to the HIV-1, Human Interaction Database

Pathways from PubChem

Interactions

Products Interactant Other Gene Complex Source Pubs Description

General gene information

Markers

Homology

Clone Names

  • FLJ95925

Gene Ontology Provided by GOA

Function Evidence Code Pubs
enables ATP binding IEA
Inferred from Electronic Annotation
more info
 
enables DNA-binding transcription factor binding ISS
Inferred from Sequence or Structural Similarity
more info
 
enables identical protein binding IPI
Inferred from Physical Interaction
more info
PubMed 
enables peptidoglycan binding TAS
Traceable Author Statement
more info
PubMed 
enables protein binding IPI
Inferred from Physical Interaction
more info
PubMed 
enables sequence-specific DNA binding ISS
Inferred from Sequence or Structural Similarity
more info
 
Process Evidence Code Pubs
involved_in apoptotic process NAS
Non-traceable Author Statement
more info
PubMed 
involved_in cellular response to lipopolysaccharide IDA
Inferred from Direct Assay
more info
PubMed 
involved_in cellular response to lipopolysaccharide IMP
Inferred from Mutant Phenotype
more info
PubMed 
involved_in defense response TAS
Traceable Author Statement
more info
PubMed 
involved_in detection of biotic stimulus TAS
Traceable Author Statement
more info
PubMed 
involved_in inflammatory response IMP
Inferred from Mutant Phenotype
more info
PubMed 
involved_in innate immune response IEA
Inferred from Electronic Annotation
more info
 
involved_in leukocyte migration involved in inflammatory response IEA
Inferred from Electronic Annotation
more info
 
involved_in negative regulation of NF-kappaB transcription factor activity IDA
Inferred from Direct Assay
more info
PubMed 
involved_in negative regulation of NIK/NF-kappaB signaling IBA
Inferred from Biological aspect of Ancestor
more info
PubMed 
involved_in negative regulation of NIK/NF-kappaB signaling IDA
Inferred from Direct Assay
more info
PubMed 
involved_in negative regulation of acute inflammatory response IMP
Inferred from Mutant Phenotype
more info
PubMed 
involved_in negative regulation of inflammatory response IMP
Inferred from Mutant Phenotype
more info
PubMed 
involved_in negative regulation of interleukin-1 beta production IMP
Inferred from Mutant Phenotype
more info
PubMed 
involved_in positive regulation of NF-kappaB transcription factor activity IDA
Inferred from Direct Assay
more info
PubMed 
involved_in positive regulation of NF-kappaB transcription factor activity IPI
Inferred from Physical Interaction
more info
PubMed 
involved_in positive regulation of T-helper 2 cell cytokine production ISS
Inferred from Sequence or Structural Similarity
more info
 
involved_in positive regulation of T-helper 2 cell differentiation ISS
Inferred from Sequence or Structural Similarity
more info
 
involved_in positive regulation of cysteine-type endopeptidase activity involved in apoptotic process IBA
Inferred from Biological aspect of Ancestor
more info
PubMed 
involved_in positive regulation of cysteine-type endopeptidase activity involved in apoptotic process IDA
Inferred from Direct Assay
more info
PubMed 
involved_in positive regulation of interleukin-1 beta production IDA
Inferred from Direct Assay
more info
PubMed 
involved_in positive regulation of interleukin-1 beta production IMP
Inferred from Mutant Phenotype
more info
PubMed 
involved_in positive regulation of interleukin-4 production ISS
Inferred from Sequence or Structural Similarity
more info
 
involved_in positive regulation of transcription by RNA polymerase II ISS
Inferred from Sequence or Structural Similarity
more info
 
involved_in positive regulation of type 2 immune response ISS
Inferred from Sequence or Structural Similarity
more info
 
involved_in protein deubiquitination TAS
Traceable Author Statement
more info
 
involved_in purinergic nucleotide receptor signaling pathway TAS
Traceable Author Statement
more info
 
involved_in response to ethanol IEA
Inferred from Electronic Annotation
more info
 
involved_in response to organic cyclic compound IEA
Inferred from Electronic Annotation
more info
 
involved_in signal transduction NAS
Non-traceable Author Statement
more info
PubMed 
Component Evidence Code Pubs
located_in Golgi membrane IDA
Inferred from Direct Assay
more info
PubMed 
part_of NLRP3 inflammasome complex IDA
Inferred from Direct Assay
more info
PubMed 
located_in cytoplasm IDA
Inferred from Direct Assay
more info
PubMed 
located_in cytoplasm TAS
Traceable Author Statement
more info
PubMed 
located_in cytosol TAS
Traceable Author Statement
more info
 
located_in endoplasmic reticulum IEA
Inferred from Electronic Annotation
more info
 
located_in extracellular region IEA
Inferred from Electronic Annotation
more info
 
located_in nucleus ISS
Inferred from Sequence or Structural Similarity
more info
 

General protein information

Preferred Names
NACHT, LRR and PYD domains-containing protein 3
Names
NACHT domain-, leucine-rich repeat-, and PYD-containing protein 3
NACHT, LRR and PYD containing protein 3
PYRIN-containing APAF1-like protein 1
caterpiller protein 1.1
cold autoinflammatory syndrome 1 protein
cold-induced autoinflammatory syndrome 1 protein
cryopyrin
cryopyrin, NACHT, LRR and PYD domains - containing protein 3
deafness, autosomal dominant 34
nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 3

NCBI Reference Sequences (RefSeq)

NEW Try the new Transcript table

RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

  1. NG_007509.2 RefSeqGene

    Range
    4984..37936
    Download
    GenBank, FASTA, Sequence Viewer (Graphics), LRG_197

mRNA and Protein(s)

  1. NM_001079821.3NP_001073289.2  NACHT, LRR and PYD domains-containing protein 3 isoform e

    Status: REVIEWED

    Description
    Transcript Variant: This variant (3) differs in the 5' UTR, compared to variant 6. Both variants 3 and 6 encode the same isoform (e).
    Source sequence(s)
    AC104335, AF410477, AK314998, AL606804
    Related
    ENSP00000375704.4, ENST00000391828.8
    Conserved Domains (7) summary
    cd00116
    Location:573949
    LRR_RI; Leucine-rich repeats (LRRs), ribonuclease inhibitor (RI)-like subfamily. LRRs are 20-29 residue sequence motifs present in many proteins that participate in protein-protein interactions and have different functions and cellular locations. LRRs correspond ...
    cd08320
    Location:891
    Pyrin_NALPs; Pyrin death domain found in NALP proteins
    sd00033
    Location:741769
    LRR_RI; leucine-rich repeat [structural motif]
    pfam05729
    Location:218387
    NACHT; NACHT domain
    pfam14484
    Location:142207
    FISNA; Fish-specific NACHT associated domain
    pfam17779
    Location:464518
    NOD2_WH; NOD2 winged helix domain
    cl39015
    Location:8831029
    LRR_RI; Leucine-rich repeats (LRRs), ribonuclease inhibitor (RI)-like subfamily. LRRs are 20-29 residue sequence motifs present in many proteins that participate in protein-protein interactions and have different functions and cellular locations. LRRs correspond ...
  2. NM_001127461.3NP_001120933.2  NACHT, LRR and PYD domains-containing protein 3 isoform c

    Status: REVIEWED

    Description
    Transcript Variant: This variant (4) differs in the 5' UTR and lacks an alternate in-frame exon in the 3' coding region, compared to variant 6. The encoded isoform (c) is shorter than isoform e.
    Source sequence(s)
    AB208891, AC104335, AK314998
    Consensus CDS
    CCDS44346.1
    Related
    ENSP00000355453.2, ENST00000366497.6
    Conserved Domains (6) summary
    cd00116
    Location:573977
    LRR_RI; Leucine-rich repeats (LRRs), ribonuclease inhibitor (RI)-like subfamily. LRRs are 20-29 residue sequence motifs present in many proteins that participate in protein-protein interactions and have different functions and cellular locations. LRRs correspond ...
    cd08320
    Location:891
    Pyrin_NALPs; Pyrin death domain found in NALP proteins
    sd00033
    Location:741762
    LRR_RI; leucine-rich repeat [structural motif]
    pfam05729
    Location:218387
    NACHT; NACHT domain
    pfam14484
    Location:142207
    FISNA; Fish-specific NACHT associated domain
    pfam17779
    Location:464518
    NOD2_WH; NOD2 winged helix domain
  3. NM_001127462.3NP_001120934.2  NACHT, LRR and PYD domains-containing protein 3 isoform d

    Status: REVIEWED

    Description
    Transcript Variant: This variant (5) lacks an alternate in-frame exon in the mid-coding region, compared to variant 6. The encoded isoform (d) is shorter than isoform e.
    Source sequence(s)
    AC104335, AF410477, AL606804, AY422168
    Consensus CDS
    CCDS44347.1
    Related
    ENSP00000375703.3, ENST00000391827.3
    Conserved Domains (8) summary
    smart00368
    Location:909936
    LRR_RI; Leucine rich repeat, ribonuclease inhibitor type
    cd00116
    Location:573892
    LRR_RI; Leucine-rich repeats (LRRs), ribonuclease inhibitor (RI)-like subfamily. LRRs are 20-29 residue sequence motifs present in many proteins that participate in protein-protein interactions and have different functions and cellular locations. LRRs correspond ...
    cd08320
    Location:891
    Pyrin_NALPs; Pyrin death domain found in NALP proteins
    sd00033
    Location:741769
    LRR_RI; leucine-rich repeat [structural motif]
    sd00034
    Location:697717
    LRR_AMN1; leucine-rich repeat [structural motif]
    pfam05729
    Location:218387
    NACHT; NACHT domain
    pfam14484
    Location:142207
    FISNA; Fish-specific NACHT associated domain
    pfam17779
    Location:464518
    NOD2_WH; NOD2 winged helix domain
  4. NM_001243133.2NP_001230062.1  NACHT, LRR and PYD domains-containing protein 3 isoform e

    See identical proteins and their annotated locations for NP_001230062.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (6) represents the longest transcript and encodes isoform e. Variants 1 and 6 represent the same transcript but use different translation start sites since both sites are likely used. The encoded isoform (e) uses the most conserved translation start site. Both variants 3 and 6 encode the same isoform (e).
    Source sequence(s)
    AC104335, AF410477, AF427617
    UniProtKB/Swiss-Prot
    Q96P20
    Related
    ENSP00000337383.4, ENST00000336119.8
    Conserved Domains (7) summary
    cd00116
    Location:573949
    LRR_RI; Leucine-rich repeats (LRRs), ribonuclease inhibitor (RI)-like subfamily. LRRs are 20-29 residue sequence motifs present in many proteins that participate in protein-protein interactions and have different functions and cellular locations. LRRs correspond ...
    cd08320
    Location:891
    Pyrin_NALPs; Pyrin death domain found in NALP proteins
    sd00033
    Location:741769
    LRR_RI; leucine-rich repeat [structural motif]
    pfam05729
    Location:218387
    NACHT; NACHT domain
    pfam14484
    Location:142207
    FISNA; Fish-specific NACHT associated domain
    pfam17779
    Location:464518
    NOD2_WH; NOD2 winged helix domain
    cl39015
    Location:8831029
    LRR_RI; Leucine-rich repeats (LRRs), ribonuclease inhibitor (RI)-like subfamily. LRRs are 20-29 residue sequence motifs present in many proteins that participate in protein-protein interactions and have different functions and cellular locations. LRRs correspond ...
  5. NM_004895.5NP_004886.3  NACHT, LRR and PYD domains-containing protein 3 isoform a

    See identical proteins and their annotated locations for NP_004886.3

    Status: REVIEWED

    Description
    Transcript Variant: This variant (1) represents the same transcript, but uses an upstream translation start codon, compared to variant 6. Variants 1 and 6 represent the same transcript but use different translation start sites since both sites are likely used. The encoded isoform (a) uses a less conserved upstream translation start codon and has a slightly longer N-terminus, compared to isoform e.
    Source sequence(s)
    AC104335, AF410477, AF427617
    Consensus CDS
    CCDS1632.1
    UniProtKB/Swiss-Prot
    Q96P20
    Conserved Domains (5) summary
    cd00116
    Location:575951
    LRR_RI; Leucine-rich repeats (LRRs), ribonuclease inhibitor (RI)-like subfamily. LRRs are 20-29 residue sequence motifs present in many proteins that participate in protein-protein interactions and have different functions and cellular locations. LRRs correspond ...
    cd08320
    Location:1093
    Pyrin_NALPs; Pyrin death domain found in NALP proteins
    sd00033
    Location:743771
    LRR_RI; leucine-rich repeat [structural motif]
    pfam05729
    Location:220389
    NACHT; NACHT domain
    pfam14484
    Location:144209
    FISNA; Fish-specific NACHT associated domain
  6. NM_183395.3NP_899632.2  NACHT, LRR and PYD domains-containing protein 3 isoform b

    Status: REVIEWED

    Description
    Transcript Variant: This variant (2) lacks two alternate in-frame exons, which are located in the mid-coding and 3' coding regions, compared to variant 6. The encoded isoform (b) is shorter than isoform e.
    Source sequence(s)
    AC104335, AF410477, AF427617, AL606804, AY092033
    Consensus CDS
    CCDS1633.1
    Related
    ENSP00000294752.4, ENST00000348069.7
    Conserved Domains (7) summary
    cd00116
    Location:573920
    LRR_RI; Leucine-rich repeats (LRRs), ribonuclease inhibitor (RI)-like subfamily. LRRs are 20-29 residue sequence motifs present in many proteins that participate in protein-protein interactions and have different functions and cellular locations. LRRs correspond ...
    cd08320
    Location:891
    Pyrin_NALPs; Pyrin death domain found in NALP proteins
    sd00033
    Location:741769
    LRR_RI; leucine-rich repeat [structural motif]
    sd00034
    Location:697717
    LRR_AMN1; leucine-rich repeat [structural motif]
    pfam05729
    Location:218387
    NACHT; NACHT domain
    pfam14484
    Location:142207
    FISNA; Fish-specific NACHT associated domain
    pfam17779
    Location:464518
    NOD2_WH; NOD2 winged helix domain

RefSeqs of Annotated Genomes: Homo sapiens Updated Annotation Release 109.20210514

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p13 Primary Assembly

Genomic

  1. NC_000001.11 Reference GRCh38.p13 Primary Assembly

    Range
    247416163..247448823
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_017000182.1XP_016855671.1  NACHT, LRR and PYD domains-containing protein 3 isoform X1

    UniProtKB/Swiss-Prot
    Q96P20
    Conserved Domains (5) summary
    cd00116
    Location:575951
    LRR_RI; Leucine-rich repeats (LRRs), ribonuclease inhibitor (RI)-like subfamily. LRRs are 20-29 residue sequence motifs present in many proteins that participate in protein-protein interactions and have different functions and cellular locations. LRRs correspond ...
    cd08320
    Location:1093
    Pyrin_NALPs; Pyrin death domain found in NALP proteins
    sd00033
    Location:743771
    LRR_RI; leucine-rich repeat [structural motif]
    pfam05729
    Location:220389
    NACHT; NACHT domain
    pfam14484
    Location:144209
    FISNA; Fish-specific NACHT associated domain
  2. XM_017000181.1XP_016855670.1  NACHT, LRR and PYD domains-containing protein 3 isoform X1

    UniProtKB/Swiss-Prot
    Q96P20
    Conserved Domains (5) summary
    cd00116
    Location:575951
    LRR_RI; Leucine-rich repeats (LRRs), ribonuclease inhibitor (RI)-like subfamily. LRRs are 20-29 residue sequence motifs present in many proteins that participate in protein-protein interactions and have different functions and cellular locations. LRRs correspond ...
    cd08320
    Location:1093
    Pyrin_NALPs; Pyrin death domain found in NALP proteins
    sd00033
    Location:743771
    LRR_RI; leucine-rich repeat [structural motif]
    pfam05729
    Location:220389
    NACHT; NACHT domain
    pfam14484
    Location:144209
    FISNA; Fish-specific NACHT associated domain
  3. XM_011544048.2XP_011542350.1  NACHT, LRR and PYD domains-containing protein 3 isoform X1

    See identical proteins and their annotated locations for XP_011542350.1

    UniProtKB/Swiss-Prot
    Q96P20
    Conserved Domains (5) summary
    cd00116
    Location:575951
    LRR_RI; Leucine-rich repeats (LRRs), ribonuclease inhibitor (RI)-like subfamily. LRRs are 20-29 residue sequence motifs present in many proteins that participate in protein-protein interactions and have different functions and cellular locations. LRRs correspond ...
    cd08320
    Location:1093
    Pyrin_NALPs; Pyrin death domain found in NALP proteins
    sd00033
    Location:743771
    LRR_RI; leucine-rich repeat [structural motif]
    pfam05729
    Location:220389
    NACHT; NACHT domain
    pfam14484
    Location:144209
    FISNA; Fish-specific NACHT associated domain
  4. XM_024452862.1XP_024308630.1  NACHT, LRR and PYD domains-containing protein 3 isoform X3

    Conserved Domains (6) summary
    cd00116
    Location:575922
    LRR_RI; Leucine-rich repeats (LRRs), ribonuclease inhibitor (RI)-like subfamily. LRRs are 20-29 residue sequence motifs present in many proteins that participate in protein-protein interactions and have different functions and cellular locations. LRRs correspond ...
    cd08320
    Location:1093
    Pyrin_NALPs; Pyrin death domain found in NALP proteins
    sd00033
    Location:743771
    LRR_RI; leucine-rich repeat [structural motif]
    sd00034
    Location:699719
    LRR_AMN1; leucine-rich repeat [structural motif]
    pfam05729
    Location:220389
    NACHT; NACHT domain
    pfam14484
    Location:144209
    FISNA; Fish-specific NACHT associated domain
  5. XM_024452874.1XP_024308642.1  NACHT, LRR and PYD domains-containing protein 3 isoform X5

    Conserved Domains (5) summary
    cd00116
    Location:575865
    LRR_RI; Leucine-rich repeats (LRRs), ribonuclease inhibitor (RI)-like subfamily. LRRs are 20-29 residue sequence motifs present in many proteins that participate in protein-protein interactions and have different functions and cellular locations. LRRs correspond ...
    cd08320
    Location:1093
    Pyrin_NALPs; Pyrin death domain found in NALP proteins
    sd00033
    Location:743771
    LRR_RI; leucine-rich repeat [structural motif]
    pfam05729
    Location:220389
    NACHT; NACHT domain
    pfam14484
    Location:144209
    FISNA; Fish-specific NACHT associated domain
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