NLRP12

Summary

NLRP12 (NLR family pyrin domain containing 12, HGNC:22938) is a protein-coding gene on chromosome 19q13.42, encoding NACHT, LRR and PYD domains-containing protein 12 (P59046). Plays an essential role as an potent mitigator of inflammation.

This gene encodes a member of the CATERPILLER family of cytoplasmic proteins. The encoded protein, which contains an N-terminal pyrin domain, a NACHT domain, a NACHT-associated domain, and a C-terminus leucine-rich repeat region, functions as an attenuating factor of inflammation by suppressing inflammatory responses in activated monocytes. Mutations in this gene cause familial cold autoinflammatory syndrome type 2. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 91662 — RefSeq curated summary.

At a glance

• Gene–disease (curated): familial cold autoinflammatory syndrome 2 (Strong, GenCC)
• GWAS associations: 7
• Clinical variants (ClinVar): 1,490 total — 2 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 22
• MANE Select transcript: NM_144687

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:22938
Approved symbol	NLRP12
Name	NLR family pyrin domain containing 12
Location	19q13.42
Locus type	gene with protein product
Status	Approved
Aliases	RNO2, PYPAF7, Monarch1, PAN6, CLR19.3
Ensembl gene	ENSG00000142405
Ensembl biotype	protein_coding
OMIM	609648
Entrez	91662

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 11 protein_coding, 1 retained_intron

ENST00000324134, ENST00000345770, ENST00000391772, ENST00000391773, ENST00000391775, ENST00000492915, ENST00000917905, ENST00000917906, ENST00000956367, ENST00000956368, ENST00000956369, ENST00000956370

RefSeq mRNA: 3 — MANE Select: NM_144687 NM_001277126, NM_001277129, NM_144687

CCDS: CCDS12864, CCDS62784, CCDS62785

Canonical transcript exons

ENST00000324134 — 10 exons

Exon	Start	End
ENSE00001184678	53798243	53798413
ENSE00001246069	53807495	53807665
ENSE00001431069	53793741	53794136
ENSE00001913702	53823886	53824314
ENSE00003014358	53814908	53814988
ENSE00003223511	53809587	53811288
ENSE00003527450	53803952	53804122
ENSE00003544911	53805280	53805450
ENSE00003560662	53795859	53796029
ENSE00003646271	53801227	53801397

Expression profiles

Bgee: expression breadth ubiquitous, 117 present calls, max score 90.79.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 2.1691 / max 193.3725, expressed in 153 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
182564	2.1691	153

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
blood	UBERON:0000178	90.79	gold quality
monocyte	CL:0000576	90.63	gold quality
leukocyte	CL:0000738	90.40	gold quality
granulocyte	CL:0000094	86.82	gold quality
secondary oocyte	CL:0000655	83.87	gold quality
buccal mucosa cell	CL:0002336	82.14	gold quality
trabecular bone tissue	UBERON:0002483	79.33	silver quality
oocyte	CL:0000023	78.92	silver quality
bone marrow cell	CL:0002092	78.71	gold quality
bone marrow	UBERON:0002371	77.75	gold quality
spleen	UBERON:0002106	69.64	gold quality
vermiform appendix	UBERON:0001154	64.43	gold quality
right lung	UBERON:0002167	63.40	gold quality
upper lobe of left lung	UBERON:0008952	61.47	gold quality
cartilage tissue	UBERON:0002418	60.71	gold quality
upper lobe of lung	UBERON:0008948	59.89	gold quality
caecum	UBERON:0001153	59.16	gold quality
endothelial cell	CL:0000115	58.57	gold quality
upper leg skin	UBERON:0004262	57.41	silver quality
esophagus squamous epithelium	UBERON:0006920	56.88	gold quality
smooth muscle tissue	UBERON:0001135	56.47	gold quality
skin of hip	UBERON:0001554	56.41	silver quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	56.33	gold quality
lung	UBERON:0002048	56.29	gold quality
biceps brachii	UBERON:0001507	56.04	gold quality
nasal cavity epithelium	UBERON:0005384	55.79	gold quality
palpebral conjunctiva	UBERON:0001812	55.56	gold quality
amniotic fluid	UBERON:0000173	55.24	gold quality
decidua	UBERON:0002450	54.22	gold quality
placenta	UBERON:0001987	54.17	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.32

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PRDM1

miRNA regulators (miRDB)

6 targeting NLRP12, 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-4731-5P	99.89	67.23	2537
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-3059-3P	96.71	67.08	606
HSA-MIR-4695-3P	96.71	67.21	836
HSA-MIR-6858-3P	96.37	64.41	771
HSA-MIR-4435	95.90	65.47	1201

Literature-anchored findings (GeneRIF, showing 40)

• regulates activation of NF-kappa B and caspase-1-dependent cytokine processing (PMID:12019269)
• Monarch-1 enhances nonclassical and classical major histocompatibility complex class I expression at the level of the promoter, RNA, and protein expression. (PMID:12759408)
• Monarch-1 associates with IRAK-1 but not MyD88, resulting in the blockage of IRAK-1 hyperphosphorylation (PMID:16203735)
• Monarch-1 inhibits CD40-mediated activation of NF-kappaB via the non-canonical pathway in human monocytes. This inhibition stems from the ability of Monarch-1 to associate with and induce proteasome-mediated degradation of NF-kappaB inducing kinase (PMID:17237370)
• Heat shock protein 90 is a critical regulator of Monarch-1 anti-inflammatory activity (PMID:17947705)
• ATP binding by NLRP12 is critical for its inhibitory function. (PMID:18160710)
• Two mutations, nonsense and splice site, were identified in NALP12 in two families with periodic fever syndromes. (PMID:18230725)
• 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)
• Even with a variable range of associated manifestations, the extreme sensitivity to cold represents the main clinical hallmark in an individual carrying the p.D294E mutation of the NLRP12 gene. (PMID:21360512)
• NLRP12 missense mutation in periodic fever syndromes; study provides evidence of deleterious effect of an NLRP12 missense mutation; this newly identified molecular defect emphasizes the crucial role played by NLRP12 in autoinflammation (PMID:21538323)
• The authors report the first in vitro confirmed non-homotypic interaction between NLRP12 pyrin domain and the pro-apoptotic protein Fas-associated factor 1 (FAF-1), which links the innate immune system to apoptotic signaling. (PMID:21978668)
• Letter: NLRP12 mutations associated with familial cold autoinflammatory syndrome 2 in Italian patients. (PMID:24064030)
• We will focus on NLRP6 and NLRP12. (PMID:24338634)
• NLRP12/NLRP3-dependent activation of caspase-1 is likely to be a key event in mediating systemic production of IL-1beta and hypersensitivity to secondary bacterial infection during malaria. (PMID:24453977)
• This study suggested that NLRP12 mutations might account for a small fraction of common variable immunodeficiency patients with severe auto-inflammatory complications. (PMID:25064839)
• The genetics, expression and roles of NLRP12 in inflammatory signaling, host defense, and carcinogenesis are reviewed. Review. (PMID:25249449)
• Variants of NLRP12 were associated with common variable immunodeficiency. (PMID:26122175)
• This process involved the upregulation of NLRP12. (PMID:26329693)
• The novel findings reveal the critical role of NLRP12-IL-17A-CXCL1 axis in host defense by modulating neutrophil recruitment against Klebsiella pneumoniae. (PMID:26349659)
• NLRX1, NLRP12 and NLRC3 negatively modulate the host immune response following virus exposure. (Review) (PMID:26763980)
• all of the reported mutations were found to have occurred in a highly conserved region in the NACHT domain coding sequence in NLRP12 exon 3, suggesting that a screening strategy for Familial cold autoinflammatory syndrome should focus on this area of the gene (PMID:27314497)
• report the crystal structure of NLRP12 PYD domain at 1.70 A fused with an maltose-binding protein (MBP) tag (PMID:29293680)
• Patients with NLRP12 germline mutations and diagnosis of NLRP12-related autoinflammatory disease demonstrated highly variable clinical phenotypes. (PMID:29500522)
• The obesity in humans correlates with reduced expression of adipose tissue NLRP12. (PMID:30212649)
• In a cohort of Vietnam War veterans (n = 299) NLRP12 polymorphisms were analysed for association with depression and coronary calcium scores. The NLRP12 polymorphism, rs34436714 was associated with a higher DASS21 Score for depression (p = 0.037). NLRP12 polymorphisms rs34971363 and rs6509825 (p = 0.022 and p = 0.020) were associated with raised coronary calcium score. (PMID:30551324)
• We aimed to investigate the impact of the single nucleotide polymorphisms of rs34436714 of the NOD-like receptor protein 12 gene on the production of tumor necrosis factor-alpha (TNFalpha) in patients with inflammatory bowel disease (IBD) (PMID:31169706)
• Differential Expression Profile of NLRs and AIM2 in Glioma and Implications for NLRP12 in Glioblastoma. (PMID:31186453)
• The clinical phenotype and genotype of NLRP12-autoinflammatory disease: a Chinese case series with literature review. (PMID:31820221)
• Crosstalk between NLRP12 and JNK during Hepatocellular Carcinoma. (PMID:31941025)
• Nucleotide binding domain and leucine-rich repeat pyrin domain-containing protein 12: characterization of its binding to hematopoietic cell kinase. (PMID:32226298)
• A Novel Role for the Regulatory Nod-Like Receptor NLRP12 in Anti-Dengue Virus Response. (PMID:34956178)
• NLRP12-associated systemic autoinflammatory diseases in children. (PMID:35123508)
• Rare mutations in NLRP3 and NLRP12 associated with familial cold autoinflammatory syndrome: two Chinese pedigrees. (PMID:35852776)
• High expression of NLRP12 predicts poor prognosis in patients with intracranial glioma. (PMID:36599143)
• The role of NLRP12 in inflammatory diseases. (PMID:37572944)
• NLRP12 downregulates the Wnt/beta-catenin pathway via interaction with STK38 to suppress colorectal cancer. (PMID:37581937)
• NLRP12-associated autoinflammatory disease: much more than the FCAS phenotype. (PMID:37877365)
• NLRP12 Senses the SARS-CoV-2 Membrane Protein and Promotes an Inflammatory Response. (PMID:37976229)
• NLRP12-associated autoinflammatory disease in Chinese adult patients: a single-centre study. (PMID:38123482)
• The contributions of deleterious rare alleles in NLRP12 and inflammasome-related genes to polymyalgia rheumatica. (PMID:38177227)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Nlrp12	ENSMUSG00000078817
rattus_norvegicus	Nlrp12	ENSRNOG00000060745

Paralogs (20): NLRP2 (ENSG00000022556), NLRP1 (ENSG00000091592), NOD1 (ENSG00000106100), NLRC5 (ENSG00000140853), 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 12 — P59046 (reviewed: P59046)

Alternative names: Monarch-1, PYRIN-containing APAF1-like protein 7, Regulated by nitric oxide

All UniProt accessions (3): P59046, A0A0C4DFY3, A0A0C4DH17

UniProt curated annotations — full annotation on UniProt →

Function. Plays an essential role as an potent mitigator of inflammation. Primarily expressed in dendritic cells and macrophages, inhibits both canonical and non-canonical NF-kappa-B and ERK activation pathways. Functions as a negative regulator of NOD2 by targeting it to degradation via the proteasome pathway. In turn, promotes bacterial tolerance. Also inhibits the RIGI-mediated immune signaling against RNA viruses by reducing the E3 ubiquitin ligase TRIM25-mediated ‘Lys-63’-linked RIGI activation but enhancing the E3 ubiquitin ligase RNF125-mediated ‘Lys-48’-linked RIGI degradation. Also acts as a negative regulator of inflammatory response to mitigate obesity and obesity-associated diseases in adipose tissue.

Subunit / interactions. Interacts (via pyrin domain) with ASC. Interacts (via pyrin domain) with FAF1 (via UBA domain). Interacts with MAP3K14; this interaction promotes proteasomal degradation of MAP3K14. Interacts with NOD2; this interaction promotes degradation of NOD2 through the ubiquitin-proteasome pathway. Interacts with HSPA1A and HSPA8. Interacts with HSP90AA1. Interacts with TRIM25; this interaction inhibits RIGI-mediated signaling pathway.

Subcellular location. Cytoplasm.

Tissue specificity. Detected only in peripheral blood leukocytes, predominantly in eosinophils and granulocytes, and at lower levels in monocytes.

Disease relevance. Familial cold autoinflammatory syndrome 2 (FCAS2) [MIM:611762] A rare autosomal dominant systemic inflammatory 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.

Induction. By nitric oxide and DMSO in HL-60 cells, an acute myeloid leukemia cell line.

Similarity. Belongs to the NLRP family.

Isoforms (7)

UniProt ID	Names	Canonical?
P59046-1	1, I	yes
P59046-2	2, II
P59046-3	3, III
P59046-4	4, IV
P59046-5	5, rno-2
P59046-6	6
P59046-7	7

RefSeq proteins (3): NP_001264055, NP_001264058, NP_653288* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001611	Leu-rich_rpt	Repeat
IPR004020	DAPIN	Domain
IPR007111	NACHT_NTPase	Domain
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR029495	NACHT-assoc	Domain
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR041075	NOD1/2_WH	Domain
IPR041267	NLRP_HD2	Domain
IPR050637	NLRP_innate_immun_reg	Family

Pfam: PF02758, PF05729, PF13516, PF14484, PF17776, PF17779

UniProt features (33 total): repeat 8, splice variant 8, helix 6, domain 3, sequence variant 2, turn 2, chain 1, binding site 1, sequence conflict 1, strand 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
4XHS	X-RAY DIFFRACTION	1.7
5H7N	X-RAY DIFFRACTION	1.85
2L6A	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P59046-F1	81.29	0.43

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): 217–224

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-9705671	SARS-CoV-2 activates/modulates innate and adaptive immune responses
R-HSA-1643685	Disease
R-HSA-5663205	Infectious disease
R-HSA-9679506	SARS-CoV Infections
R-HSA-9694516	SARS-CoV-2 Infection
R-HSA-9705683	SARS-CoV-2-host interactions
R-HSA-9824446	Viral Infection Pathways

MSigDB gene sets: 174 (showing top): GOBP_NEGATIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, GOBP_DENDRITIC_CELL_MIGRATION, GOBP_NEGATIVE_REGULATION_OF_INTERLEUKIN_1_PRODUCTION, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_INTERLEUKIN_1_PRODUCTION, GOBP_NEGATIVE_REGULATION_OF_MAPK_CASCADE, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_NEGATIVE_REGULATION_OF_INTERLEUKIN_6_PRODUCTION, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_LEUKOCYTE_MIGRATION, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_POSITIVE_REGULATION_OF_NON_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION

GO Biological Process (20): negative regulation of cytokine production (GO:0001818), signal transduction (GO:0007165), negative regulation of signal transduction (GO:0009968), regulation of interleukin-18 production (GO:0032661), negative regulation of interleukin-1 production (GO:0032692), negative regulation of interleukin-6 production (GO:0032715), positive regulation of interleukin-1 beta production (GO:0032731), dendritic cell migration (GO:0036336), regulation of canonical NF-kappaB signal transduction (GO:0043122), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), positive regulation of MHC class I biosynthetic process (GO:0045345), negative regulation of Toll signaling pathway (GO:0045751), regulation of inflammatory response (GO:0050727), negative regulation of inflammatory response (GO:0050728), positive regulation of inflammatory response (GO:0050729), ERK1 and ERK2 cascade (GO:0070371), negative regulation of ERK1 and ERK2 cascade (GO:0070373), cellular response to cytokine stimulus (GO:0071345), negative regulation of non-canonical NF-kappaB signal transduction (GO:1901223), positive regulation of non-canonical NF-kappaB signal transduction (GO:1901224)

GO Molecular Function (5): ATP binding (GO:0005524), protein-macromolecule adaptor activity (GO:0030674), cysteine-type endopeptidase activator activity (GO:0140608), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (2): cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
SARS-CoV-2-host interactions	1
Disease	1
Viral Infection Pathways	1
SARS-CoV Infections	1
SARS-CoV-2 Infection	1
Infectious disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
inflammatory response	3
regulation of cytokine production	2
negative regulation of cytokine production	2
canonical NF-kappaB signal transduction	2
negative regulation of intracellular signal transduction	2
regulation of inflammatory response	2
non-canonical NF-kappaB signal transduction	2
regulation of non-canonical NF-kappaB signal transduction	2
cellular anatomical structure	2
cytokine production	1
negative regulation of gene expression	1
negative regulation of multicellular organismal process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
signal transduction	1
regulation of signal transduction	1
negative regulation of cell communication	1
negative regulation of signaling	1
negative regulation of response to stimulus	1
interleukin-18 production	1
interleukin-1 production	1
regulation of interleukin-1 production	1
interleukin-6 production	1
regulation of interleukin-6 production	1
interleukin-1 beta production	1
regulation of interleukin-1 beta production	1
positive regulation of interleukin-1 production	1
mononuclear cell migration	1
regulation of intracellular signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of macromolecule biosynthetic process	1
MHC class I biosynthetic process	1
regulation of MHC class I biosynthetic process	1
Toll signaling pathway	1
regulation of Toll signaling pathway	1
negative regulation of signal transduction	1
regulation of defense response	1

Protein interactions and networks

STRING

1349 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NLRP12	NLRC4	Q9NPP4	995
NLRP12	CASP1	P29466	989
NLRP12	NLRP6	P59044	985
NLRP12	NLRP1	Q9C000	985
NLRP12	NLRP3	Q96P20	983
NLRP12	AIM2	O14862	981
NLRP12	NLRP7	Q8WX94	980
NLRP12	NLRP2	Q9NX02	925
NLRP12	MEFV	O15553	909
NLRP12	PYCARD	Q9ULZ3	895
NLRP12	TRAF3	Q13114	838
NLRP12	IFI16	Q16666	798
NLRP12	NLRP4	Q96MN2	758
NLRP12	NAIP	Q13075	741
NLRP12	PYDC1	Q8WXC3	740

IntAct

86 interactions, top by confidence:

A	B	Type	Score
NLRP12	TRAF3IP3	psi-mi:“MI:0915”(physical association)	0.510
NLRP12	HCK	psi-mi:“MI:0915”(physical association)	0.510
HCK	NLRP12	psi-mi:“MI:0915”(physical association)	0.510
NLRP12	HCK	psi-mi:“MI:0915”(physical association)	0.460
HCK	NLRP12	psi-mi:“MI:0403”(colocalization)	0.460
rep	NLRP12	psi-mi:“MI:0570”(protein cleavage)	0.440
NLRP12	rep	psi-mi:“MI:0570”(protein cleavage)	0.440
Dlg4	NLRP12	psi-mi:“MI:0407”(direct interaction)	0.440
NLRP12	EIF3A	psi-mi:“MI:0915”(physical association)	0.400
NLRP12	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
Hck	NLRP12	psi-mi:“MI:0915”(physical association)	0.400
FKBP5	NLRP12	psi-mi:“MI:0915”(physical association)	0.400
MLF1	NLRP12	psi-mi:“MI:0915”(physical association)	0.400
NLRP12	Hacd3	psi-mi:“MI:0915”(physical association)	0.400
MLF2	NLRP12	psi-mi:“MI:0915”(physical association)	0.400
NLRP12	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.400
	NLRP12	psi-mi:“MI:0915”(physical association)	0.400
HSF2	NLRP12	psi-mi:“MI:0915”(physical association)	0.400
NLRP12	NUDCD3	psi-mi:“MI:0915”(physical association)	0.400
NLRP12	PSMD2	psi-mi:“MI:0915”(physical association)	0.400
NLRP12	SGTA	psi-mi:“MI:0915”(physical association)	0.400
Usp19	NLRP12	psi-mi:“MI:0915”(physical association)	0.400
NLRP12	HSP90AA1	psi-mi:“MI:0915”(physical association)	0.400
NLRP12	STIP1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (16): NLRP12 (Affinity Capture-Western), TRIM25 (Affinity Capture-Western), NLRP12 (Biochemical Activity), EIF3A (Proximity Label-MS), HIST1H2BH (Proximity Label-MS), NLRP12 (Affinity Capture-RNA), NLRP12 (Negative Genetic), NLRP12 (Affinity Capture-Western), M (Affinity Capture-Western), M (Co-localization), FAF1 (Two-hybrid), NLRP12 (Affinity Capture-Western), HSPA4 (Affinity Capture-MS), NLRP12 (Affinity Capture-Western), NLRP12 (Affinity Capture-Western)

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: A0A2H5Q1B8, P59046, Q6Q4D0, Q96MN2, A1Z198, A6QLE5, A8Y3R9, B0FPE9, D4A523, D9I2F9, D9I2G1, D9I2G3, D9I2G4, D9I2H0, E9Q5R7, P10775, P13489, P29315, P59044, P59047, Q0GKD5, Q2LKU9, Q2LKV2, Q2LKV5, Q2LKW6, Q5RAV7, Q63035, Q6B966, Q86W24, Q86W25, Q86W26, Q8CCN1, Q8HXK9, Q8HZP9, Q8R4B8, Q91VI7, Q91WS2, Q96P20, Q9C000, Q9EPB4

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 73 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	5	20.6×	1e-03
Estrogen-dependent gene expression	5	8.1×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of ERAD pathway	5	66.2×	6e-06
ERAD pathway	5	13.5×	4e-03
protein folding	8	12.3×	8e-05
protein stabilization	8	8.0×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1490 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	7
Uncertain significance	926
Likely benign	338
Benign	65

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
567880	NM_144687.4(NLRP12):c.2791G>T (p.Glu931Ter)	Pathogenic
574410	NM_144687.4(NLRP12):c.2574_2585+13del	Pathogenic
1687186	NM_144687.4(NLRP12):c.770del (p.Gln257fs)	Likely pathogenic
1711851	NM_144687.4(NLRP12):c.957del (p.Thr320fs)	Likely pathogenic
2650412	NM_144687.4(NLRP12):c.268C>T (p.Gln90Ter)	Likely pathogenic
3393657	NM_144687.4(NLRP12):c.1861C>T (p.Gln621Ter)	Likely pathogenic
3891841	NM_144687.4(NLRP12):c.2715_2716del (p.Cys905_Glu906delinsTer)	Likely pathogenic
623961	NM_144687.4(NLRP12):c.2586G>A (p.Trp862Ter)	Likely pathogenic
808638	NM_144687.4(NLRP12):c.2186_2187insTT (p.Val730fs)	Likely pathogenic

SpliceAI

1299 predictions. Top by Δscore:

Variant	Effect	Δscore
19:53798237:GCTCA:G	donor_loss	1.0000
19:53798238:CTCAC:C	donor_loss	1.0000
19:53798239:TCA:T	donor_loss	1.0000
19:53798240:CACCA:C	donor_loss	1.0000
19:53798241:A:T	donor_loss	1.0000
19:53798242:CCA:C	donor_gain	1.0000
19:53801220:GACTC:G	donor_loss	1.0000
19:53801221:ACTCA:A	donor_loss	1.0000
19:53801222:CTCAC:C	donor_loss	1.0000
19:53801223:TCA:T	donor_loss	1.0000
19:53801224:CACCG:C	donor_loss	1.0000
19:53801226:C:CG	donor_loss	1.0000
19:53801226:CCG:C	donor_gain	1.0000
19:53805276:TCAC:T	donor_loss	1.0000
19:53805277:CA:C	donor_loss	1.0000
19:53805278:A:AC	donor_gain	1.0000
19:53805278:AC:A	donor_loss	1.0000
19:53805279:C:CT	donor_gain	1.0000
19:53805279:CTG:C	donor_gain	1.0000
19:53805279:CTGA:C	donor_gain	1.0000
19:53805447:CAGC:C	acceptor_gain	1.0000
19:53805448:AGC:A	acceptor_gain	1.0000
19:53805449:GC:G	acceptor_gain	1.0000
19:53805450:CC:C	acceptor_gain	1.0000
19:53805451:C:CA	acceptor_loss	1.0000
19:53805451:C:CC	acceptor_gain	1.0000
19:53805451:C:T	acceptor_gain	1.0000
19:53805456:G:C	acceptor_gain	1.0000
19:53805456:G:GC	acceptor_gain	1.0000
19:53809582:CTTA:C	donor_loss	1.0000

AlphaMissense

6947 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:53810123:G:C	F512L	0.995
19:53810123:G:T	F512L	0.995
19:53810125:A:G	F512L	0.995
19:53801301:A:C	N894K	0.991
19:53801301:A:T	N894K	0.991
19:53809973:G:C	F562L	0.991
19:53809973:G:T	F562L	0.991
19:53809975:A:G	F562L	0.991
19:53798317:G:C	N951K	0.990
19:53798317:G:T	N951K	0.990
19:53798320:G:C	F950L	0.990
19:53798320:G:T	F950L	0.990
19:53798322:A:G	F950L	0.990
19:53810124:A:G	F512S	0.988
19:53810265:G:T	A465E	0.988
19:53810990:C:A	K223N	0.988
19:53810990:C:G	K223N	0.988
19:53798323:A:C	S949R	0.987
19:53798323:A:T	S949R	0.987
19:53798325:T:G	S949R	0.987
19:53801302:T:A	N894I	0.987
19:53810994:C:T	G222D	0.987
19:53810231:A:C	F476L	0.986
19:53810231:A:T	F476L	0.986
19:53810233:A:G	F476L	0.986
19:53801227:C:G	R919P	0.985
19:53810111:A:C	S516R	0.985
19:53810111:A:T	S516R	0.985
19:53810113:T:G	S516R	0.985
19:53810232:A:G	F476S	0.985

dbSNP variants (sampled 300 via entrez): RS1000050361 (19:53806423 C>G), RS1000112186 (19:53798735 C>G), RS1000166202 (19:53808224 ATTTAT>A), RS1000211554 (19:53805966 G>A), RS1000218324 (19:53803048 C>T), RS1000365466 (19:53813275 G>A,T), RS1000365875 (19:53800729 T>A,C), RS1000468466 (19:53795973 C>T), RS1000545899 (19:53807196 C>A,T), RS1000552122 (19:53802107 A>G), RS1000659639 (19:53807427 TTG>T), RS1000737446 (19:53801917 A>G), RS1000799004 (19:53800879 C>T), RS1000801593 (19:53797203 C>T), RS1000855492 (19:53816829 A>G)

Disease associations

OMIM: gene MIM:609648 | disease phenotypes: MIM:611762, MIM:616414

GenCC curated gene-disease

Disease	Classification	Inheritance
familial cold autoinflammatory syndrome 2	Strong	Autosomal dominant

Mondo (5): familial cold autoinflammatory syndrome 2 (MONDO:0012724), autoinflammatory syndrome (MONDO:0019751), childhood-onset schizophrenia (MONDO:0957430), autoimmune interstitial lung disease-arthritis syndrome (MONDO:0014629), periodic fever syndrome (MONDO:0015137)

Orphanet (5): NLRP12-associated hereditary periodic fever syndrome (Orphanet:247868), Autoinflammatory syndrome (Orphanet:93665), Childhood-onset schizophrenia (Orphanet:641496), Autoimmune interstitial lung disease-arthritis syndrome (Orphanet:444092), Periodic fever syndrome (Orphanet:101995)

HPO phenotypes

22 total (22 of 22 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000407	Sensorineural hearing impairment
HP:0000988	Skin rash
HP:0001025	Urticaria
HP:0001369	Arthritis
HP:0001744	Splenomegaly
HP:0001954	Recurrent fever
HP:0001974	Increased total leukocyte count
HP:0002027	Abdominal pain
HP:0002315	Headache
HP:0002716	Lymphadenopathy
HP:0002829	Arthralgia
HP:0003326	Myalgia
HP:0003565	Elevated erythrocyte sedimentation rate
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0003829	Typified by incomplete penetrance
HP:0011107	Recurrent aphthous stomatitis
HP:0011227	Elevated circulating C-reactive protein concentration
HP:0012219	Erythema nodosum
HP:0012514	Lower limb pain
HP:0033050	Pharyngalgia

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST004608_141	Granulocyte percentage of myeloid white cells	2.000000e-61
GCST004609_155	Monocyte percentage of white cells	5.000000e-80
GCST004625_219	Monocyte count	5.000000e-63
GCST004635_40	Testicular germ cell tumor	1.000000e-08
GCST011983_20	Fasting glucose	3.000000e-06
GCST90002393_672	Monocyte count	2.000000e-162
GCST90002394_565	Monocyte percentage of white cells	3.000000e-183

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007997	granulocyte percentage of myeloid white cells
EFO:0007989	monocyte percentage of leukocytes
EFO:0005091	monocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567090	Familial Cold Autoinflammatory Syndrome 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

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

Chemical	Actions (top 5)	PubMed papers
4-phenylenediamine	decreases expression, increases expression, affects binding, increases reaction	2
Benzo(a)pyrene	decreases methylation, increases methylation, affects methylation, decreases expression	2
Dinitrochlorobenzene	affects binding, increases reaction, affects localization, decreases expression	2
Oxygen	decreases reaction, increases expression	2
Tobacco Smoke Pollution	increases expression	2
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
nickel chloride	decreases expression, decreases reaction	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
lipopolysaccharide, E. coli O26-B6	decreases expression, decreases reaction	1
abrine	increases expression	1
3,5-bis(2-fluorobenzylidene)piperidin-4-one	decreases reaction, increases expression	1
Bortezomib	increases expression, increases reaction	1
Resveratrol	decreases reaction, increases expression	1
Arsenic Trioxide	increases expression, increases reaction	1
Air Pollutants	affects expression, increases abundance	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	affects methylation	1
Cadmium	increases expression	1
Curcumin	decreases reaction, increases expression	1
Drugs, Chinese Herbal	increases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression, affects response to substance, increases expression	1
Methapyrilene	increases methylation	1
Naphthoquinones	increases expression	1
Nickel	decreases expression	1
Ozone	affects expression, increases abundance	1
Pentachlorophenol	affects expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00442182	PHASE2	UNKNOWN	The Efficacy and Safety of ITF2357 in AIS
NCT05027373	PHASE1	UNKNOWN	Safety, Tolerability and Pharmacokinetic of Recombinant Anti-IL-1β Humanized Monoclonal Antibody Injection
NCT00887939	Not specified	COMPLETED	Pathogenesis of Physical Induced Urticarial Syndromes
NCT03510442	Not specified	RECRUITING	Natural History, Genetics, and Pathophysiology of Systemic Juvenile Idiopathic Arthritis, Adult-Onset Still’s Disease, and Related Conditions
NCT06248957	Not specified	RECRUITING	SYSTEMS-LEVEL ANALYSES OF IMMUNE DYSREGULATION
NCT05995288	Not specified	COMPLETED	Homeopathic Treatment of Children Suffering From PFAPA