NLRC4

Summary

NLRC4 (NLR family CARD domain containing 4, HGNC:16412) is a protein-coding gene on chromosome 2p22.3, encoding NLR family CARD domain-containing protein 4 (Q9NPP4). Key component of inflammasomes that indirectly senses specific proteins from pathogenic bacteria and fungi and responds by assembling an inflammasome complex that promotes caspase-1 activation, cytokine production and macrophage pyroptosis.

This gene encodes a member of the caspase recruitment domain-containing NLR family. Family members play essential roles in innate immune response to a wide range of pathogenic organisms, tissue damage and other cellular stresses. Mutations in this gene result in autoinflammation with infantile enterocolitis. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 58484 — RefSeq curated summary.

At a glance

• Gene–disease (curated): periodic fever-infantile enterocolitis-autoinflammatory syndrome (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 6
• Clinical variants (ClinVar): 940 total — 6 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 30
• Druggable target: yes
• MANE Select transcript: NM_001199138

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16412
Approved symbol	NLRC4
Name	NLR family CARD domain containing 4
Location	2p22.3
Locus type	gene with protein product
Status	Approved
Aliases	CLAN1, ipaf, CLANA, CLANB, CLANC, CLAND, CLR2.1, CLAN
Ensembl gene	ENSG00000091106
Ensembl biotype	protein_coding
OMIM	606831
Entrez	58484

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 nonsense_mediated_decay

ENST00000342905, ENST00000360906, ENST00000402280, ENST00000404025, ENST00000652197, ENST00000894701, ENST00000894702

RefSeq mRNA: 4 — MANE Select: NM_001199138 NM_001199138, NM_001199139, NM_001302504, NM_021209

CCDS: CCDS33174, CCDS77400

Canonical transcript exons

ENST00000402280 — 9 exons

Exon	Start	End
ENSE00000743510	32241033	32241125
ENSE00001006616	32249607	32251601
ENSE00001426717	32224453	32224765
ENSE00001548450	32264738	32264886
ENSE00001615005	32252419	32252679
ENSE00003841676	32236247	32236339
ENSE00003842818	32235401	32235568
ENSE00003845591	32238132	32238302
ENSE00003970304	32256775	32256893

Expression profiles

Bgee: expression breadth ubiquitous, 166 present calls, max score 93.82.

FANTOM5 (CAGE): breadth broad, TPM avg 1.2079 / max 123.1183, expressed in 283 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
27706	0.7874	257
27708	0.2045	56
27709	0.1600	72
27707	0.0559	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	93.82	gold quality
leukocyte	CL:0000738	93.42	gold quality
blood	UBERON:0000178	87.23	gold quality
granulocyte	CL:0000094	85.80	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.65	gold quality
trabecular bone tissue	UBERON:0002483	82.46	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.35	gold quality
bone marrow	UBERON:0002371	81.18	gold quality
bone marrow cell	CL:0002092	80.57	gold quality
spleen	UBERON:0002106	79.77	gold quality
vermiform appendix	UBERON:0001154	79.34	gold quality
right lung	UBERON:0002167	72.79	gold quality
buccal mucosa cell	CL:0002336	72.62	silver quality
upper lobe of left lung	UBERON:0008952	71.00	gold quality
caecum	UBERON:0001153	70.97	gold quality
upper lobe of lung	UBERON:0008948	70.37	gold quality
apex of heart	UBERON:0002098	69.67	gold quality
oviduct epithelium	UBERON:0004804	67.55	silver quality
lung	UBERON:0002048	67.05	gold quality
smooth muscle tissue	UBERON:0001135	66.48	gold quality
right adrenal gland	UBERON:0001233	66.45	gold quality
omental fat pad	UBERON:0010414	65.82	gold quality
left adrenal gland	UBERON:0001234	65.78	gold quality
peritoneum	UBERON:0002358	65.75	gold quality
lymph node	UBERON:0000029	65.68	gold quality
right adrenal gland cortex	UBERON:0035827	65.45	gold quality
left adrenal gland cortex	UBERON:0035825	65.39	gold quality
gall bladder	UBERON:0002110	65.29	gold quality
adipose tissue of abdominal region	UBERON:0007808	65.07	gold quality
gastrocnemius	UBERON:0001388	65.06	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-9801	yes	6.64
E-ANND-3	no	3.34

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP53, TP73

Literature-anchored findings (GeneRIF, showing 40)

• Apaf-1 protein expression did not correlate with Apaf-1 mRNA levels in human leukaemic blasts.Apaf-1 DNA promoter methylation might contribute to the inactivation of Apaf-1 expression (PMID:12545166)
• CLAN regulates several events central to host defense mechanisms against invading bacteria: modulating relative sensitivity of macrophages to lipopolysaccharide and peptidoglycan, and impacting host-pathogen interactions. (PMID:15528373)
• p53 can directly induce Ipaf gene transcription, which contributes to p53-dependent apoptosis in at least some human cells (PMID:15580302)
• Involvement of caspase 1 and its activator Ipaf upstream of mitochondrial events in apoptosis (PMID:16817903)
• hNAIP and hIpaf mediate innate intracellular defense against flagellated Legionella in human cells. (PMID:18453601)
• [review] role of NLRC4 inflammasome and pathways in innate immune detection of bacterial virulence factors (PMID:20349122)
• Genetic analysis of Chromobacterium violaceum infection revealed that the TTSS needle protein CprI can stimulate NLRC4 inflammasome activation in human macrophages (PMID:21918512)
• Twelve single nucleotide polymorphisms within NLRP1, NLRP3, NLRC4, CARD8, CASP1, and IL1B genes were analyzed in 150 HIV-1-infected Brazilian subjects. (PMID:22227487)
• NLRC4 is important for host survival and bacterial clearance, as well as neutrophil-mediated inflammation in the lungs following Klebsiella pneumoniae infection. (PMID:22547706)
• the NAIP5-NLRC4 inflammasome is induced by direct interactions with conserved N- and C-terminal regions of flagellin (PMID:23012363)
• This review describes the surprisingly diverse mechanisms by which NLRC4 senses bacteria and initiates innate immune responses. (PMID:23215645)
• inflammasome (also known as NLRC4) has been demonstrated to play a role in host defense mechanisms against pathogen-associated molecules (PMID:24054992)
• Data show that the disease was caused by a de novo gain-of-function mutation in NLR family CARD domain containing 4 (NLRC4) encoding a p.Val341Ala substitution. (PMID:25217960)
• Elevated expression of IPAF was associated with inflammation in patients with pemphigus vulgaris disease. (PMID:25342284)
• Data indicate that NLR family CARD domain containing 4 protein (NLRC4) is a causative gene for familial cold autoinflammatory syndrome (FCAS). (PMID:25385754)
• cN-II co-immunoprecipitated both with wild type Ipaf and its LRR domain after transfection with corresponding expression vectors, but not with Ipaf lacking the LRR domain. (PMID:25811392)
• analysis of a subset of inflammasome receptors including NLRP3, NLRC4 and AIM2 that triggers formation of the micrometer-sized spherical supramolecular complex called the ASC speck (PMID:26258904)
• Thus, pathogenic inflammasome activity during Candida infection is negatively regulated by the IL-22/NLRC4/IL-1Ra axis. (PMID:26269955)
• association of IL-18 levels with a single nucleotide polymorphism in the untranslated exon 2 of the inflammasome component NLRC4 (PMID:26362438)
• While both contributing to pathogen clearance, NLRP3 more than NLRC4 contributes to deleterious inflammatory responses in cystic fibrosis and correlates with defective NLRC4-dependent IL-1Ra production. (PMID:26972847)
• LPS activates the MAPK pathway in macrophages, thus resulting in the upregulation of NLRC4; however, NLRC4 inhibits IL1beta and IL18 production, contributing to the anti-inflammatory response. (PMID:27175981)
• The authors describe a novel mutation in NLRC4 in a large pedigree causing an NLRC4-associated, partially anakinra-responsive AID, dominated by cutaneous erythematous nodes and urticarial rash, arthralgias, and late-onset enterocolitis. (PMID:27203668)
• Results found that NLRC4 expression increased in for promoting DN progression and demonstrate NLRC4-driven IL-1beta production as critical for the progression of DN. (PMID:27706238)
• obesity-associated NLRC4 inflammasome activation/ interleukin-1 signalling promotes breast cancer progression in humans and in mouse models (PMID:27708283)
• mRNA expression levels of NLRP1 and NLRC4 were not altered in chronic hepatitis B patients, suggesting that these genes are not responsible for the impaired immune responses against HBV observed in these patients. (PMID:27750030)
• Ubiquitin-tagged NLRC4 could induce cell death and activate caspase-8 independent of Ser(533) phosphorylation. Our (PMID:27974463)
• High expression of NLRP3, NLRC4, and CASP1 in background non-tumorous liver is significantly correlated with poor prognosis of patients after resection of hepatocellular carcinoma. (PMID:28011505)
• this study shows that human NAIP-NLRC4-inflammasome senses the Pseudomonas aeruginosa T3SS inner-rod protein (PMID:28992059)
• Study findings suggest that NLRC4 may be involved in the exacerbation or modification of psoriatic lesions. (PMID:29797527)
• Cryo-EM structures of ASC and NLRC4 CARD filaments reveal a unified mechanism of nucleation and activation of caspase-1 (PMID:30279182)
• Salmonella employs the Salmonella pathogenicity island-2 type III secretion system to subvert Salmonella pathogenicity island-1 induced NLRP3 and NLRC4 inflammasome responses in human primary macrophages. (PMID:30368901)
• The structure revealed that the helical architecture of the NLRC4(CARD) filament is essentially identical to that of the downstream filament assembled by the CARD of caspase-1 (casp1(CARD)), but deviates from the split washer-like assembly of the NAIP.NLRC4 oligomer. (PMID:30385506)
• Loss-of-function NLRC4 SNP is associated with better treatment response in MS patients. (PMID:30658261)
• Differential expression pattern of various of NLRP3, NLRC4 and NLRP6 inflammasomes were observed in primary immune thrombocytopenia patients. (PMID:30802690)
• The increase in TNF-alpha during nonalcoholic fatty liver disease promotes the activation of the NLRC4 inflammasome, which increases the production of IL-18 and IL-1beta and triggers pyroptosis. (PMID:30824190)
• Upregulation of the NLRC4 inflammasome contributes to poor prognosis in glioma patients. (PMID:31133717)
• Flagellin/NLRC4 Pathway Rescues NLRP3-Inflammasome Defect in Dendritic Cells From HIV-Infected Patients: Perspective for New Adjuvant in Immunocompromised Individuals. (PMID:31244842)
• The NLRC4 inflammasome activation and subsequent IL-18 production favors bacterial persistence by inhibiting antimicrobial peptide production and, at the same time, contributes to gastric inflammation. (PMID:31511355)
• The results identify HSC70 as a negative regulator of caspase-1 activation by the temperature-sensitive NLRC4-H443P mutant. (PMID:31597739)
• A Common NLRC4 Gene Variant Associates With Inflammation and Pulmonary Function in Human Immunodeficiency Virus and Tuberculosis. (PMID:31751447)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	birc5b	ENSDARG00000055655
mus_musculus	Nlrc4	ENSMUSG00000039193
rattus_norvegicus	Nlrc4	ENSRNOG00000005810
drosophila_melanogaster	Diap2	FBGN0015247
caenorhabditis_elegans		WBGENE00000250

Paralogs (7): BIRC3 (ENSG00000023445), BIRC5 (ENSG00000089685), BIRC7 (ENSG00000101197), XIAP (ENSG00000101966), BIRC2 (ENSG00000110330), BIRC6 (ENSG00000115760), NAIP (ENSG00000249437)

Protein

Protein identifiers

NLR family CARD domain-containing protein 4 — Q9NPP4 (reviewed: Q9NPP4)

Alternative names: CARD, LRR, and NACHT-containing protein, Caspase recruitment domain-containing protein 12, Ice protease-activating factor

All UniProt accessions (3): Q9NPP4, A0A494BZZ1, A0A499FIV7

UniProt curated annotations — full annotation on UniProt →

Function. Key component of inflammasomes that indirectly senses specific proteins from pathogenic bacteria and fungi and responds by assembling an inflammasome complex that promotes caspase-1 activation, cytokine production and macrophage pyroptosis. The NLRC4 inflammasome is activated as part of the innate immune response to a range of intracellular bacteria.

Subunit / interactions. Homooligomer; homooligomerizes to induce formation of the NLRC4 inflammasome. Homooligomerizes following activation by pathogenic proteins. Component of the NLRC4 inflammasome, at least composed of NLRC4 and caspase-1 (CASP1). Some NLRC4 inflammasomes contain PYCARD/ASC, while some others directly contact and activate CASP1. Interacts (via CARD domain) with PYCARD/ASC, pro-caspase-1 (CASP1), NOD2, BCL10 and NALP1 (NAC) by CARD-CARD interaction. Interacts with EIF2AK2/PKR.

Subcellular location. Cytoplasm. Cytosol. Inflammasome.

Tissue specificity. Isoform 2 is expressed ubiquitously, although highly expressed in lung and spleen. Isoform 1 is highly expressed in lung, followed by leukocytes especially monocytes, lymph node, colon, brain, prostate, placenta, spleen, bone marrow and fetal liver. Isoform 4 is only detected in brain.

Post-translational modifications. Phosphorylated at Ser-533 following infection of macrophages with S.typhimurium (Salmonella). Phosphorylation is essential for NLRC4 inflammasome function to promote caspase-1 activation and pyroptosis. PRKCD phosphorylates Ser-533 in vitro.

Disease relevance. Autoinflammation with infantile enterocolitis (AIFEC) [MIM:616050] An autosomal dominant disorder characterized by neonatal-onset enterocolitis, periodic fever, and fatal or near-fatal episodes of autoinflammation. Affected individuals tend to have poor overall growth and gastrointestinal symptoms in infancy, recurrent febrile episodes with splenomegaly, and sometimes hematologic disturbances, arthralgias, or myalgias. The disease is caused by variants affecting the gene represented in this entry. Familial cold autoinflammatory syndrome 4 (FCAS4) [MIM:616115] A form of autoinflammatory syndrome, a rare autosomal dominant systemic disease characterized by recurrent episodes of maculopapular rash associated with arthralgias, myalgias, fever and chills, swelling of the extremities, and conjunctivitis after generalized exposure to cold. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. In an autoinhibited form the C-terminal leucine-rich repeat (LRR) domain is positioned to sterically occlude one side of the NBD domain and consequently sequester NLRC4 in a monomeric state. An ADP-mediated interaction between the NBD and the WHD also contributes to the autoinhibition.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9NPP4-1	1, CLANA	yes
Q9NPP4-2	2, CLANB
Q9NPP4-3	3, CLANC
Q9NPP4-4	4, CLAND

RefSeq proteins (4): NP_001186067, NP_001186068, NP_001289433, NP_067032 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001315	CARD	Domain
IPR007111	NACHT_NTPase	Domain
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR040535	NLRC4_HD	Domain
IPR042220	NLRC4	Family
IPR053882	Nlrc4-like_WHD	Domain

Pfam: PF00619, PF05729, PF17889, PF22524

UniProt features (39 total): repeat 12, sequence conflict 6, helix 6, splice variant 5, sequence variant 3, domain 2, region of interest 2, chain 1, binding site 1, modified residue 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
6K8J	ELECTRON MICROSCOPY	3.3
6MKS	ELECTRON MICROSCOPY	3.4
6N1I	ELECTRON MICROSCOPY	3.58
8FVU	ELECTRON MICROSCOPY	3.6
8FW2	ELECTRON MICROSCOPY	3.8
8FW9	ELECTRON MICROSCOPY	4.46

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NPP4-F1	85.18	0.45

Functional residue map

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

Ligand- & substrate-binding residues (1): 169–176

Post-translational modifications (1): 533

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-6803207	TP53 Regulates Transcription of Caspase Activators and Caspases
R-HSA-844623	The IPAF inflammasome

MSigDB gene sets: 223 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GOBP_POSITIVE_REGULATION_OF_PROTEIN_MATURATION, MODULE_451, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, REACTOME_INFLAMMASOMES, REACTOME_NUCLEOTIDE_BINDING_DOMAIN_LEUCINE_RICH_REPEAT_CONTAINING_RECEPTOR_NLR_SIGNALING_PATHWAYS, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_DETECTION_OF_OTHER_ORGANISM, GOBP_INTERLEUKIN_1_PRODUCTION, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_PROTEIN_MATURATION

GO Biological Process (17): activation of innate immune response (GO:0002218), pattern recognition receptor signaling pathway (GO:0002221), apoptotic process (GO:0006915), inflammatory response (GO:0006954), positive regulation of protein processing (GO:0010954), detection of bacterium (GO:0016045), positive regulation of interleukin-1 beta production (GO:0032731), defense response to bacterium (GO:0042742), positive regulation of apoptotic process (GO:0043065), innate immune response (GO:0045087), icosanoid biosynthetic process (GO:0046456), positive regulation of inflammatory response (GO:0050729), obsolete positive regulation of NF-kappaB transcription factor activity (GO:0051092), protein homooligomerization (GO:0051260), pyroptotic inflammatory response (GO:0070269), immune system process (GO:0002376), regulation of apoptotic process (GO:0042981)

GO Molecular Function (8): magnesium ion binding (GO:0000287), ATP binding (GO:0005524), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), endopeptidase activator activity (GO:0061133), caspase binding (GO:0089720), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (5): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), canonical inflammasome complex (GO:0061702), IPAF inflammasome complex (GO:0072557)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
TP53 Regulates Transcription of Cell Death Genes	1
Inflammasomes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
defense response	2
response to bacterium	2
apoptotic process	2
inflammatory response	2
cellular anatomical structure	2
activation of immune response	1
positive regulation of innate immune response	1
innate immune response-activating signaling pathway	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
protein processing	1
positive regulation of proteolysis	1
regulation of protein processing	1
positive regulation of protein maturation	1
detection of other organism	1
interleukin-1 beta production	1
regulation of interleukin-1 beta production	1
positive regulation of interleukin-1 production	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
immune response	1
defense response to symbiont	1
icosanoid metabolic process	1
carboxylic acid biosynthetic process	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
regulation of inflammatory response	1
protein complex oligomerization	1
biological_process	1
regulation of programmed cell death	1
metal ion binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
endopeptidase activity	1
peptidase activator activity	1
endopeptidase regulator activity	1

Protein interactions and networks

STRING

1518 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NLRC4	MEFV	O15553	999
NLRC4	NLRP3	Q96P20	999
NLRC4	AIM2	O14862	999
NLRC4	CASP1	P29466	999
NLRC4	NLRP1	Q9C000	999
NLRC4	PYCARD	Q9ULZ3	998
NLRC4	NLRP6	P59044	998
NLRC4	NLRP12	P59046	995
NLRC4	NLRP7	Q8WX94	995
NLRC4	NAIP	Q13075	988
NLRC4	NLRP2	Q9NX02	974
NLRC4	BECN1	Q14457	958
NLRC4	NLRC5	Q86WI3	955
NLRC4	IL18	Q14116	940
NLRC4	IFI16	Q16666	927

IntAct

11 interactions, top by confidence:

A	B	Type	Score
NLRC4	CASP1	psi-mi:“MI:0915”(physical association)	0.740
CASP1	NLRC4	psi-mi:“MI:0915”(physical association)	0.740
NLRC4	NLRC4	psi-mi:“MI:0915”(physical association)	0.650
PYCARD	NLRC4	psi-mi:“MI:0915”(physical association)	0.550
ECE1	NLRC4	psi-mi:“MI:0915”(physical association)	0.370
NLRC4	CASP8	psi-mi:“MI:0914”(association)	0.350

BioGRID (35): PSMC5 (Affinity Capture-Western), NLRC4 (Affinity Capture-Western), NLRC4 (Affinity Capture-Western), NLRC4 (Affinity Capture-Western), NOD2 (Affinity Capture-Western), XK (Affinity Capture-Western), NOD1 (Affinity Capture-Western), NAIP (Affinity Capture-Western), NLRP3 (Affinity Capture-Western), NLRC4 (Affinity Capture-Western), NLRP1 (Affinity Capture-Western), BCL10 (Affinity Capture-Western), NLRC4 (Affinity Capture-Western), CASP1 (Affinity Capture-Western), NOD2 (Affinity Capture-Western)

ESM2 similar proteins: A0A386CAB9, A0A7H0DNF0, A2CI98, A6QR20, C6FG12, F1M649, F1MHT9, F6R2G2, O15050, O70167, O70173, P59045, Q13075, Q20CR4, Q2LKV2, Q3UIR3, Q3UP24, Q4TVR5, Q4VSN3, Q4VSN4, Q4VSN5, Q5EB20, Q5H9U9, Q5RBY8, Q5U228, Q66X01, Q66X03, Q66X05, Q66X22, Q6NU22, Q6NU51, Q6XUX0, Q6XUX1, Q6XUX2, Q6XUX3, Q6ZN28, Q7Z2W4, Q80VH0, Q8CCN1, Q8QMP8

Diamond homologs: F1M649, F1MHT9, F6R2G2, Q3UP24, Q9NPP4, Q9R1M5, Q9MZV6, Q9MZV7, Q13075, Q9JIB3, Q9JIB6, Q9QWK5, Q9R016, Q13489, O08736, O75601, O89094, P29452, P29466, P42574, P43527, P49662, P51878, P55213, P55865, P55867, P57730, P70343, P70677, Q075B4, Q08DY9, Q153Z0, Q2PFV2, Q504J1, Q5E9C1, Q5EG05, Q5IS54, Q5IS99, Q5XLA6, Q60431

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
TP53	“up-regulates quantity by expression”	NLRC4	“transcriptional regulation”
LRRK2	“up-regulates activity”	NLRC4	phosphorylation
NLRC4	“form complex”	“NLRC4 inflammasome”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	8
Uncertain significance	564
Likely benign	261
Benign	26

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
1299713	NM_001199138.2(NLRC4):c.1016T>C (p.Leu339Pro)	Pathogenic
143224	NM_001199138.2(NLRC4):c.1022T>C (p.Val341Ala)	Pathogenic
156462	NM_001199138.2(NLRC4):c.1009A>T (p.Thr337Ser)	Pathogenic
161413	NM_001199138.2(NLRC4):c.1328A>C (p.His443Pro)	Pathogenic
2429469	NM_001199138.2(NLRC4):c.1021G>T (p.Val341Leu)	Pathogenic
989330	NM_001199138.2(NLRC4):c.1021G>C (p.Val341Leu)	Pathogenic
1694356	NM_001199138.2(NLRC4):c.1015C>G (p.Leu339Val)	Likely pathogenic
1694365	NM_001199138.2(NLRC4):c.1630G>T (p.Glu544Ter)	Likely pathogenic
2664351	NM_001199138.2(NLRC4):c.390del (p.Ser132fs)	Likely pathogenic
374310	NM_001199138.2(NLRC4):c.512C>T (p.Ser171Phe)	Likely pathogenic
421649	NM_001199138.2(NLRC4):c.620G>A (p.Arg207Lys)	Likely pathogenic
636773	NM_001199138.2(NLRC4):c.1010C>A (p.Thr337Asn)	Likely pathogenic
808727	NM_001199138.2(NLRC4):c.1329C>G (p.His443Gln)	Likely pathogenic
813268	Single allele	Likely pathogenic

SpliceAI

1698 predictions. Top by Δscore:

Variant	Effect	Δscore
2:32235396:CCTA:C	donor_loss	1.0000
2:32235400:C:CG	donor_loss	1.0000
2:32235469:T:TA	donor_gain	1.0000
2:32235566:CGA:C	acceptor_gain	1.0000
2:32235569:C:CC	acceptor_gain	1.0000
2:32236245:A:AC	donor_gain	1.0000
2:32236246:C:CC	donor_gain	1.0000
2:32236246:CT:C	donor_gain	1.0000
2:32236249:A:AC	donor_gain	1.0000
2:32236249:AGTT:A	donor_gain	1.0000
2:32238127:GTTA:G	donor_loss	1.0000
2:32238128:TTAC:T	donor_loss	1.0000
2:32238129:TACCT:T	donor_loss	1.0000
2:32238130:ACCTA:A	donor_loss	1.0000
2:32238131:C:CT	donor_loss	1.0000
2:32238298:TTCAG:T	acceptor_gain	1.0000
2:32238299:TCAG:T	acceptor_gain	1.0000
2:32238300:CAG:C	acceptor_gain	1.0000
2:32238300:CAGC:C	acceptor_gain	1.0000
2:32238301:AG:A	acceptor_gain	1.0000
2:32238303:C:CC	acceptor_gain	1.0000
2:32238303:CTGAA:C	acceptor_loss	1.0000
2:32238310:A:AC	acceptor_gain	1.0000
2:32238310:A:C	acceptor_gain	1.0000
2:32238313:A:C	acceptor_gain	1.0000
2:32241028:CTGAC:C	donor_loss	1.0000
2:32241031:A:AT	donor_loss	1.0000
2:32241032:C:T	donor_loss	1.0000
2:32241035:A:AC	donor_gain	1.0000
2:32241036:G:C	donor_gain	1.0000

AlphaMissense

6838 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:32251359:C:G	G169R	0.985
2:32251359:C:T	G169R	0.985
2:32251034:A:T	V277D	0.984
2:32250541:G:C	F441L	0.983
2:32250541:G:T	F441L	0.983
2:32250543:A:G	F441L	0.983
2:32250513:C:G	A451P	0.982
2:32251359:C:A	G169W	0.979
2:32224535:A:G	W1005R	0.978
2:32224535:A:T	W1005R	0.978
2:32250506:C:G	R453P	0.977
2:32251130:A:G	F245S	0.977
2:32251438:C:A	K142N	0.977
2:32251438:C:G	K142N	0.977
2:32251462:G:C	F134L	0.977
2:32251462:G:T	F134L	0.977
2:32251464:A:G	F134L	0.977
2:32250500:A:G	L455P	0.976
2:32251308:A:G	W186R	0.976
2:32251308:A:T	W186R	0.976
2:32250674:G:T	A397D	0.974
2:32250831:A:G	C345R	0.974
2:32249789:A:G	L692P	0.972
2:32250523:C:A	Q447H	0.972
2:32250523:C:G	Q447H	0.972
2:32251340:T:A	K175M	0.972
2:32224688:A:G	W954R	0.968
2:32224688:A:T	W954R	0.968
2:32251349:C:T	G172D	0.968
2:32250512:G:T	A451E	0.967

dbSNP variants (sampled 300 via entrez): RS1000006583 (2:32237046 A>G), RS1000036639 (2:32262513 G>A), RS1000237434 (2:32253035 A>G), RS1000246401 (2:32258780 C>G,T), RS1000306719 (2:32235640 G>A), RS1000318981 (2:32241558 T>C), RS1000348330 (2:32224154 A>T), RS1000416455 (2:32225449 A>C,G), RS1000672490 (2:32246573 A>C,G), RS1000729429 (2:32245595 A>G), RS1000772284 (2:32253278 T>C), RS1000882348 (2:32252190 A>G), RS1000913583 (2:32229529 T>C), RS1001099166 (2:32251908 T>C), RS1001182445 (2:32265627 T>C)

Disease associations

OMIM: gene MIM:606831 | disease phenotypes: MIM:616050, MIM:616115, MIM:603165

GenCC curated gene-disease

Disease	Classification	Inheritance
periodic fever-infantile enterocolitis-autoinflammatory syndrome	Strong	Autosomal dominant
familial cold autoinflammatory syndrome 4	Strong	Autosomal dominant

Mondo (4): periodic fever-infantile enterocolitis-autoinflammatory syndrome (MONDO:0014472), familial cold autoinflammatory syndrome 4 (MONDO:0014498), autoinflammatory syndrome (MONDO:0019751), atopic eczema (MONDO:0004980)

Orphanet (4): Periodic fever-infantile enterocolitis-autoinflammatory syndrome (Orphanet:436166), Familial cold urticaria (Orphanet:47045), NLRC4-related familial cold autoinflammatory syndrome (Orphanet:576349), Autoinflammatory syndrome (Orphanet:93665)

HPO phenotypes

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

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000988	Skin rash
HP:0001025	Urticaria
HP:0001287	Meningitis
HP:0001508	Failure to thrive
HP:0001744	Splenomegaly
HP:0001873	Thrombocytopenia
HP:0001876	Pancytopenia
HP:0001903	Anemia
HP:0001945	Fever
HP:0001954	Recurrent fever
HP:0002572	Episodic vomiting
HP:0002829	Arthralgia
HP:0003073	Hypoalbuminemia
HP:0003281	Increased circulating ferritin concentration
HP:0003326	Myalgia
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0004322	Short stature
HP:0004387	Enterocolitis
HP:0005208	Secretory diarrhea
HP:0005521	Disseminated intravascular coagulation
HP:0008872	Feeding difficulties in infancy
HP:0011227	Elevated circulating C-reactive protein concentration
HP:0011473	Villous atrophy
HP:0011900	Hypofibrinogenemia
HP:0012177	Abnormal natural killer cell physiology
HP:0012378	Fatigue
HP:0025420	Diffuse alveolar hemorrhage
HP:0040218	Reduced total natural killer cell count

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002255_2	Inflammatory biomarkers	3.000000e-19
GCST004441_28	Interleukin-18 levels	2.000000e-22
GCST006661_237	Male-pattern baldness	7.000000e-26
GCST006661_314	Male-pattern baldness	4.000000e-20
GCST009731_25	Blood protein levels in cardiovascular risk	9.000000e-10
GCST009736_3	Interleukin-18 levels	1.000000e-15

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004812	interleukin-1 beta measurement
EFO:0004581	interleukin 18 measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D003876	Dermatitis, Atopic	C16.320.850.210; C17.800.174.193; C17.800.815.193; C17.800.827.210; C20.543.480.343

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630857 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Nickel	decreases expression, increases expression	2
Particulate Matter	increases abundance, increases expression, decreases expression	2
aristolochic acid I	increases expression	1
bisphenol A	decreases methylation	1
titanium dioxide	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
zinc sulfide	increases expression, affects cotreatment	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
cadmium selenide	affects cotreatment, increases expression	1
CGP 52608	affects binding, increases reaction	1
jinfukang	decreases expression, affects cotreatment	1
NSC 689534	affects binding, increases expression	1
Arsenic Trioxide	decreases expression	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	affects cotreatment, decreases expression	1
Copper	affects binding, increases expression	1
Succimer	affects cotreatment, increases expression	1
Estradiol	affects cotreatment, increases expression	1
Iron	increases expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression, affects cotreatment	1
Menthol	decreases expression	1
Methapyrilene	increases methylation	1
Silver	affects expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	increases expression	1

ChEMBL screening assays

13 unique, capped per target: 13 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4628095	Binding	Inhibition of NLRC4 inflammasome (unknown origin) activation in bone marrow derived macrophages assessed as inhibition of Salmonella-induced IL-1beta secretion at 5 uM by ELISA	Discovery and optimization of 4-oxo-2-thioxo-thiazolidinones as NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inhibitors. — Bioorg Med Chem Lett

Cellosaurus cell lines

9 cell lines: 7 cancer cell line, 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0406	MAIL8-3	Transformed cell line	Female
CVCL_5I77	THP1-NLRC4	Cancer cell line	Male
CVCL_A8AR	THP1-KO-NLRC4	Cancer cell line	Male
CVCL_A8GH	CLC12N2	Cancer cell line	Male
CVCL_A8GI	NUC12N2	Cancer cell line	Female
CVCL_A8GJ	MAIL8-19	Transformed cell line	Female
CVCL_B7YI	Abcam Raji NLRC4 KO	Cancer cell line	Male
CVCL_B9Z6	Abcam THP-1 NLRC4 KO	Cancer cell line	Male
CVCL_C7AW	Abcam PC-3 NLRC4 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00106496	PHASE4	COMPLETED	A Multi-Center Study of Short and Long-term Use of Protopic Ointment in Patients With Atopic Dermatitis
NCT00117377	PHASE4	COMPLETED	Effects of Pimecrolimus Cream 1% on the Molecular and Cellular Profile of Adult Male Patients With Atopic Dermatitis
NCT00119158	PHASE4	COMPLETED	Combination Therapy for Atopic Dermatitis
NCT00120302	PHASE4	COMPLETED	Quality of Life Study in Adults With Facial Eczema
NCT00121316	PHASE4	COMPLETED	Safety and Efficacy of Pimecrolimus Cream 1% in Mild to Moderate Head and Neck Atopic Dermatitis (AD) Patients
NCT00121381	PHASE4	COMPLETED	Pimecrolimus Cream 1% Plus Topical Corticosteroid in Patients (2-17 Years of Age) With Severe Atopic Dermatitis
NCT00124709	PHASE4	TERMINATED	Safety and Efficacy of Pimecrolimus Cream 1% in Atopic Disease Modification
NCT00130364	PHASE4	COMPLETED	Efficacy and Safety of Pimecrolimus Cream 1% in Patients (2 to 11 Years Old) With Mild to Moderate Facial Atopic Dermatitis
NCT00139581	PHASE4	COMPLETED	Comparison of Pimecrolimus Cream 1% Twice-Daily to Once-Daily Dosing in the Management of Atopic Dermatitis in Pediatric Subjects
NCT00150059	PHASE4	COMPLETED	Efficacy and Safety of Pimecrolimus Cream 1% in Patients ≥ 3 Months of Age With Mild or Moderate Atopic Dermatitis
NCT00179959	PHASE4	COMPLETED	The Impact of Treating Staphylococcus Aureus Infection and Colonization on the Clinical Severity of Atopic Dermatitis
NCT00180141	PHASE4	COMPLETED	Elidel-Study: Elidel in Patients With Atopic Dermatitis
NCT00185510	PHASE4	COMPLETED	Efficacy and Safety Study of Advantan for Maintenance Treatment of Atopic Dermatitis
NCT00236106	PHASE4	COMPLETED	Short Term Growth in Children With Atopic Dermatitis
NCT00367016	PHASE4	COMPLETED	Immunologic Basis of Anti-IgE Therapy (Study II: On Patients With Asthma)
NCT00367393	PHASE4	COMPLETED	Reconstitution With Pimecrolimus Cream 1% of Steroid-damaged Skin in Adults With Atopic Dermatitis
NCT00368719	PHASE4	WITHDRAWN	Evaluation to Assess the Long Term Safety of Tacrolimus Ointment for Atopic Dermatitis
NCT00445081	PHASE4	COMPLETED	Prednisolone vs. Ciclosporine in Severe Atopic Eczema
NCT00460083	PHASE4	COMPLETED	Epiceram Versus Elidel for Treatment of Mild to Moderate Atopic Dermatitis
NCT00484003	PHASE4	COMPLETED	A Quality of Life and Safety Study With Pimecrolimus Cream, 1% in Children (Age 2-12 Years) With Atopic Dermatitis
NCT00509990	PHASE4	COMPLETED	Open Label Study of Long Term Treatment of Pediatric Treatment of Atopic Dermatitis With Pimecrolimus Cream 1% Within a Usual Clinical Setting
NCT00510003	PHASE4	COMPLETED	Assessment of Pruritus Improvement With Pimecrolimus Treatment on the Areas Affected by Mild-to-moderate AD, in Patients 2- to 11- Year-old
NCT00546000	PHASE4	COMPLETED	Cutivate Lotion HPA Axis Pediatric Study
NCT00557284	PHASE4	COMPLETED	Efficacy Study of Montelukast in Atopic Dermatitis Induced by Food Allergens
NCT00559546	PHASE4	COMPLETED	Montelukast as a Controller of Atopic Syndrome
NCT00616538	PHASE4	COMPLETED	Epiceram™ Device Versus Mid-Strength Topical Steroid (Fluticasone Propionate 0.05%) for Treatment of Atopic Dermatitis
NCT00654355	PHASE4	COMPLETED	Measuring Adherence to Topical Therapy in Children With Atopic Dermatitis and the Impact of a Return Visit
NCT00666159	PHASE4	COMPLETED	Comparison Study Between Protopic (Tacrolimus Ointment) and Elidel (Pimecrolimus Cream) in Treating Pediatric Patients With Atopic Dermatitis
NCT00666302	PHASE4	COMPLETED	A Comparison Study Between Protopic (Tacrolimus) Ointment and Elidel (Pimecrolimus) Cream in Treating Subjects With Atopic Dermatitis
NCT00667160	PHASE4	COMPLETED	Comparison Study Between Protopic (Tacrolimus Ointment) and Elidel (Pimecrolimus Cream) in Pediatric Patients With Mild Atopic Dermatitis
NCT00671528	PHASE4	TERMINATED	Safety and Efficacy of Quadriderme® in the Treatment of Impetiginous Eczema (Study P05134AM4)
NCT00673725	PHASE4	COMPLETED	Locobase® REPAIR Used as an Adjunctive to Standard Therapy in Children With Moderate to Severe Atopic Dermatitis
NCT00689832	PHASE4	COMPLETED	Protopic Ointment in Children Atopic Eczema
NCT00690105	PHASE4	COMPLETED	Protopic Ointment in Adult Atopic Eczema of the Face
NCT00690833	PHASE4	COMPLETED	Efficacy of Desonide (Desonatetm) Gel 0.05% in Younger and Older Subjects With Atopic Dermatitis
NCT00693693	PHASE4	COMPLETED	Adherence to Topical Hydrocortisone 17-butyrate 0.1% (Locoid®) Using Different Vehicles in Adults With Atopic Dermatitis
NCT00771121	PHASE4	UNKNOWN	Effect of Moisturizing Creams on Skin Barrier Function
NCT00810862	PHASE4	TERMINATED	Study of Pimecrolimus Treatment for Atopic Dermatitis of African American Children
NCT00819507	PHASE4	COMPLETED	VANOS Cream and Skin Barrier Function
NCT00822783	PHASE4	COMPLETED	Study to Determine the Effect of an Anti-IgE Agent on Inflammatory Cells in the Skin of Atopic Dermatitis Patients