NLRP6

Summary

NLRP6 (NLR family pyrin domain containing 6, HGNC:22944) is a protein-coding gene on chromosome 11p15.5, encoding NACHT, LRR and PYD domains-containing protein 6 (P59044). Acts as the sensor component of the NLRP6 inflammasome, which mediates inflammasome activation in response to various pathogen-associated signals, leading to maturation and secretion of IL1B and IL18.

The protein encoded by this gene binds arginine-vasopressin and may be involved in the arginine-vasopressin-mediated regulation of renal salt-water balance. The encoded protein also mediates inflammatory responses in the colon to allow recovery from intestinal epithelial damage and protects against tumorigenesis and the development of colitis. Finally, this protein can increase activation of NF-kappa-B, activation of CASP1 through interaction with ASC, and cAMP accumulation. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 171389 — RefSeq curated summary.

At a glance

• GWAS associations: 12
• Clinical variants (ClinVar): 287 total — 1 likely-pathogenic
• MANE Select transcript: NM_001276700

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:22944
Approved symbol	NLRP6
Name	NLR family pyrin domain containing 6
Location	11p15.5
Locus type	gene with protein product
Status	Approved
Aliases	PYPAF5, PAN3, CLR11.4
Ensembl gene	ENSG00000174885
Ensembl biotype	protein_coding
OMIM	609650
Entrez	171389

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 retained_intron

ENST00000312165, ENST00000527946, ENST00000534750

RefSeq mRNA: 2 — MANE Select: NM_001276700 NM_001276700, NM_138329

CCDS: CCDS60680, CCDS7693

Canonical transcript exons

ENST00000534750 — 8 exons

Exon	Start	End
ENSE00001207302	284230	284400
ENSE00001207311	279834	279872
ENSE00001207316	279327	279607
ENSE00001207330	280084	281839
ENSE00001292151	284475	284642
ENSE00002162986	278407	278598
ENSE00002179383	282705	282797
ENSE00002196065	285166	285388

Expression profiles

Bgee: expression breadth ubiquitous, 122 present calls, max score 86.98.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.0155 / max 204.6322, expressed in 119 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
112159	0.7881	109
112157	0.1364	8
112158	0.0910	20

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
small intestine Peyer’s patch	UBERON:0003454	86.98	gold quality
small intestine	UBERON:0002108	83.23	gold quality
blood	UBERON:0000178	76.66	gold quality
granulocyte	CL:0000094	72.47	gold quality
right lobe of liver	UBERON:0001114	69.12	gold quality
spleen	UBERON:0002106	69.09	gold quality
vermiform appendix	UBERON:0001154	66.81	gold quality
duodenum	UBERON:0002114	64.98	gold quality
left uterine tube	UBERON:0001303	62.30	gold quality
right lung	UBERON:0002167	62.20	gold quality
caecum	UBERON:0001153	61.05	gold quality
leukocyte	CL:0000738	60.69	gold quality
monocyte	CL:0000576	59.42	gold quality
lymph node	UBERON:0000029	59.35	gold quality
liver	UBERON:0002107	59.22	gold quality
adult mammalian kidney	UBERON:0000082	59.06	gold quality
body of pancreas	UBERON:0001150	57.79	gold quality
bone marrow cell	CL:0002092	57.74	gold quality
intestine	UBERON:0000160	57.59	gold quality
upper lobe of left lung	UBERON:0008952	57.48	gold quality
upper lobe of lung	UBERON:0008948	55.83	gold quality
jejunal mucosa	UBERON:0000399	54.97	gold quality
transverse colon	UBERON:0001157	54.44	gold quality
omental fat pad	UBERON:0010414	54.29	gold quality
peritoneum	UBERON:0002358	54.25	gold quality
tendon of biceps brachii	UBERON:0008188	54.06	gold quality
colonic epithelium	UBERON:0000397	53.69	gold quality
adipose tissue of abdominal region	UBERON:0007808	53.54	gold quality
myocardium	UBERON:0002349	53.49	gold quality
mucosa of stomach	UBERON:0001199	52.54	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.09

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 32)

• The dual AngII/AVP receptor gene N119S/C163R variant exhibits sodium-induced dysfunction and cosegregates with salt-sensitive hypertension in the Dahl salt-sensitive hypertensive rat model. (PMID:11984003)
• PYPAF5 functions in immune cells to coordinate the transduction of pro-inflammatory signals to the activation of NF-kappaB and pro-caspase-1 (PMID:12387869)
• AVR is distinct from Nalp6/PYPAF5 based on different mRNA and protein sizes, subcellular localization, and tissue-specific expression patterns. (PMID:18413781)
• Studies identify AVR/NAVR as key receptors involved in blood pressure regulation and sex-specific modulation of renal water homeostasis, cognitive function, and anxiety-like behavior. (PMID:20923861)
• A. actinomycetemcomitans enhances NLRP3 and reduces NLRP6 inflammasome expression. (PMID:22503597)
• NLRP6 is a newly characterized member of this family that inhibits NF-kappaB and MAP-kinase dependent immune signaling to hamper anti-microbial defense. (PMID:23811097)
• Our results revealed an association between NLRP6/AVR and ADM loci with male essential hypertension, suggesting the existence of sex-specific NLRP6/AVR and ADM variants affecting male susceptibility to essential hypertension. (PMID:24147025)
• We will focus on NLRP6 and NLRP12. (PMID:24338634)
• this review discuss recent findings related to NLRP6 activity, while highlighting outstanding questions and future perspectives in elucidating its roles in health and disease (PMID:28214100)
• Data suggest that mRNA/protein levels of NLRP6 are down-regulated in synovial tissues and synoviocytes of rheumatoid arthritis (RA) patients compared to osteoarthritis patients; NLRP6 provides docking site to facilitate interaction between TAB2/3 and TRIM38 in RA synoviocytes in response to TNFalpha. (NLRP6 = ; TAB2/3 = transforming growth factor-b-activated kinase 1-binding protein 2/3; TRIM38 = tripartite motif 38) (PMID:28295271)
• that NLRP6 exerts anti-fibrotic effects in LX-2 cells via regulating PPM1A/Smad2/3 and that NLRP6 may be an effective target in the treatment of liver fibrosis (PMID:29966662)
• Studied expression of NLR family pyrin domain containing 6 (NLRP6) in colon of patients with Hirschsprung’s disease (HSCR) and found decreased expression of NLRP6 may contribute to colonic microbiome changes and increase the susceptibility to develop Hirschsprung’s associated enterocolitis. (PMID:30262203)
• NLRP6, a member of the nucleotide-binding domain, leucine-rich repeat-containing (NLR) innate immune receptor family, participates in the progression of intestinal inflammation and enteric pathogen infections. [review] (PMID:30515917)
• Differential expression pattern of various of NLRP3, NLRC4 and NLRP6 inflammasomes were observed in primary immune thrombocytopenia patients. (PMID:30802690)
• Long noncoding RNA OIP5-AS1 aggravates cell proliferation, migration in gastric cancer by epigenetically silencing NLRP6 expression via binding EZH2. (PMID:31219209)
• Overexpression of NLRP6 in Caco-2 and IEC-6cells suppress the increase apoptosis induced by miR-650 overexpression. (PMID:31399193)
• Loss of NLRP6 expression increases the severity of acute kidney injury. (PMID:31504777)
• Candida albicans SC5314 inhibits NLRP3/NLRP6 inflammasome expression and dampens human intestinal barrier activity in Caco-2 cell monolayer model. (PMID:31629100)
• Expression of nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 6 in human dental pulp tissues and cells. (PMID:32553945)
• NLRP6 suppresses gastric cancer growth via GRP78 ubiquitination. (PMID:32682010)
• NLRP6-caspase 4 inflammasome activation in response to cariogenic bacterial lipoteichoic acid in human dental pulp inflammation. (PMID:33377178)
• A detrimental role of NLRP6 in host iron metabolism during Salmonella infection. (PMID:34942528)
• NLRP3 and NLRP6 expression in pterygium and normal conjunctiva and their relationship with pterygium formation and recurrence. (PMID:35068231)
• Defects in NLRP6, autophagy and goblet cell homeostasis are associated with reduced duodenal CRH receptor 2 expression in patients with functional dyspepsia. (PMID:35093492)
• Physiological and pathophysiological functions of NLRP6: pro- and anti-inflammatory roles. (PMID:35650327)
• A novel pyroptosis risk model composed of NLRP6 effectively predicts the prognosis of hepatocellular carcinoma patients. (PMID:35651286)
• NLRP6 potentiates PI3K/AKT signalling by promoting autophagic degradation of p85alpha to drive tumorigenesis. (PMID:37770465)
• NLRP6 deficiency suppresses colorectal cancer liver metastasis growth by modulating M-MDSC-induced immunosuppressive microenvironment. (PMID:38278335)
• Decreased expression of the NLRP6 inflammasome is associated with increased intestinal permeability and inflammation in obesity with type 2 diabetes. (PMID:38315242)
• NLRP6 negatively regulates host defense against polymicrobial sepsis. (PMID:38720893)
• This publication deals with the rat ortholog of the human NLRP6 gene. (PMID:7489366)
• This publication deals with the rat ortholog of the human NLRP6 gene. (PMID:9095083)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Nlrp6	ENSMUSG00000038745
rattus_norvegicus	Nlrp6	ENSRNOG00000045677

Paralogs (20): NLRP2 (ENSG00000022556), NLRP1 (ENSG00000091592), NOD1 (ENSG00000106100), NLRC5 (ENSG00000140853), NLRP12 (ENSG00000142405), NLRP14 (ENSG00000158077), NLRP4 (ENSG00000160505), NLRX1 (ENSG00000160703), NLRP3 (ENSG00000162711), NOD2 (ENSG00000167207), NLRP7 (ENSG00000167634), NLRC3 (ENSG00000167984), NLRP5 (ENSG00000171487), NLRP13 (ENSG00000173572), CIITA (ENSG00000179583), NLRP8 (ENSG00000179709), NLRP11 (ENSG00000179873), NLRP10 (ENSG00000182261), NLRP9 (ENSG00000185792), PYDC2 (ENSG00000253548)

Protein

Protein identifiers

NACHT, LRR and PYD domains-containing protein 6 — P59044 (reviewed: P59044)

Alternative names: Angiotensin II/vasopressin receptor, PYRIN-containing APAF1-like protein 5

All UniProt accessions (1): P59044

UniProt curated annotations — full annotation on UniProt →

Function. Acts as the sensor component of the NLRP6 inflammasome, which mediates inflammasome activation in response to various pathogen-associated signals, leading to maturation and secretion of IL1B and IL18. Inflammasomes are supramolecular complexes that assemble in the cytosol in response to pathogens and other damage-associated signals and play critical roles in innate immunity and inflammation. Acts as a recognition receptor (PRR): recognizes and binds specific pathogens and other damage-associated signals, such as lipoteichoic acid (LTA), a cell-wall component of Gram-positive bacteria, or double stranded RNA (dsRNA). May also recognize and bind lipopolysaccharide (LPS), a major component of the outer membrane of Gram-negative bacteria; however, LPS is probably not a major activator of the NLRP6 inflammasome. Following LTA- or dsRNA-binding, NLRP6 undergoes liquid-liquid phase separation (LLPS), enhancing multivalent interactions, an essential step for the formation of the NLRP6 inflammasome polymeric complex. The NLRP6 inflammasome acts by promoting recruitment of effector pro-inflammatory caspases (CASP1 and/or CASP4) that catalyze maturation and secretion of IL1B and IL18 in the extracellular milieu. The NLRP6 inflammasome plays a central role in the maintenance of epithelial integrity and host defense against microbial infections in the intestine. Required to restrict infection against Gram-positive bacteria by recognizing lipoteichoic acid (LTA), leading to recruitment of CASP4 and CASP1, and subsequent maturation and secretion of IL1B and IL18. Involved in intestinal antiviral innate immunity together with DHX15: recognizes and binds viral dsRNA to restrict infection by enteric viruses through the interferon pathway and GSDMD-dependent release of IL18. Required to prevent infection by the apicomplexan parasite Cryptosporidium in enterocytes by promoting GSDMD-dependent release of IL18. The NLRP6 inflammasome may also regulate the gut microbiota composition by acting as a sensor of microbiota-associated metabolites to form a PYCARD/ASC-dependent inflammasome for downstream IL18 release and secretion of antimicrobial peptides. Essential for gut mucosal self-renewal and proliferation. Regulate mucus secretion in an inflammasome- and autophagy-dependent manner to prevent invasion by enteric bacteria,. During systemic bacterial infections, the NLRP6 inflammasome negatively regulates neutrophil recruitment and neutrophil extracellular traps (NETs) formation. May promote peripheral nerve recovery following injury via an inflammasome-independent mechanism.

Subunit / interactions. Homomultimer; forms the NLRP6 inflammasome polymeric complex, a filament composed of homopolymers in response to pathogens and other damage-associated signals. The core of NLRP6 inflammasomes consists of a signal sensor component (NLRP6), an adapter (PYCARD/ASC), which recruits effector pro-inflammatory caspases (CASP1 and CASP4). Interacts (via pyrin domain) with PYCARD/ASC (via pyrin domain); interaction takes place following NLRP6 activation and formation of liquid-liquid phase separation (LLPS), initiating nucleation which greatly enhances further addition of soluble PYCARD/ASC molecules to the speck in a prion-like polymerization process. Clustered PYCARD/ASC nucleates the formation of CASP1 (or possibly CASP4) filaments through the interaction of their respective CARD domains, acting as a platform for CASP1 polymerization. CASP1 filament formation increases local enzyme concentration, resulting in trans-autocleavage and activation. Active CASP1 then processes IL1B and IL18 precursors, leading to the release of mature cytokines in the extracellular milieu and inflammatory response. Interacts with DHX15.

Subcellular location. Cytoplasm. Cytosol. Inflammasome. Cell membrane. Nucleus membrane.

Tissue specificity. Expressed in peripheral blood leukocytes, predominantly in granulocytes and, at lower levels, in CD4(+) and CD8(+) T-cells. Expressed in colonic myofibroblasts (at protein level).

Post-translational modifications. Polyubiquitinated with ‘Lys-63’-linked chains, promoting the interaction with PYCARD/ASC and formation of the NLRP6 inflammasome. Deubiquitination by CYLD decreases the interaction with PYCARD/ASC.

Domain organisation. The poly-Lys disordered region (352-356) mediates the formation of liquid-liquid phase separation (LLPS), an essential step for nucleation and formation of the NLRP6 inflammasome complex.

Induction. Up-regulated by rosiglitazone, a PPARG agonist, in Caco2 and HCT116 colorectal carcinoma cells. Down-regulated by CRH (at protein level).

Similarity. Belongs to the NLRP family.

Isoforms (2)

UniProt ID	Names	Canonical?
P59044-1	1	yes
P59044-2	2

RefSeq proteins (2): NP_001263629, NP_612202 (=MANE)

Domains & families (InterPro)

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

Pfam: PF02758, PF05729, PF17776, PF17779

UniProt features (34 total): mutagenesis site 10, helix 6, repeat 5, region of interest 3, sequence variant 3, domain 2, compositionally biased region 2, chain 1, binding site 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6NDJ	X-RAY DIFFRACTION	2.27
6NCV	ELECTRON MICROSCOPY	3.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P59044-F1	79.64	0.36

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): 202–209

Mutagenesis-validated functional residues (10):

Position	Phenotype
21	decreased formation of an inflammasome filament.
23	decreased formation of an inflammasome filament. decreased ability to promote pycard/asc polymerization.
27–28	abolished formation of an inflammasome filament.
39	decreased formation of an inflammasome filament. abolished ability to promote pycard/asc polymerization.
42	abolished formation of an inflammasome filament.
53	abolished formation of an inflammasome filament.
53	does not affect formation of an inflammasome filament.
71	does not prevent formation of an inflammasome filament.
87	does not prevent formation of an inflammasome filament.
352–356	impaired formation of liquid-liquid phase separation (llps).

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 424 (showing top): GOBP_NEGATIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, GOBP_REGULATION_OF_AUTOPHAGY, GOMF_RNA_NUCLEASE_ACTIVITY, GOBP_P_BODY_ASSEMBLY, GOBP_REGULATION_OF_INFLAMMATORY_RESPONSE_TO_ANTIGENIC_STIMULUS, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOMF_NUCLEASE_ACTIVITY, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_PROTEIN_TARGETING, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_TOLL_LIKE_RECEPTOR_SIGNALING_PATHWAY, GCAAGGA_MIR502, GOBP_LEUKOCYTE_MEDIATED_CYTOTOXICITY

GO Biological Process (36): acute inflammatory response to antigenic stimulus (GO:0002438), acute inflammatory response (GO:0002526), negative regulation of inflammatory response to antigenic stimulus (GO:0002862), regulation of autophagy (GO:0010506), negative regulation of type II interferon production (GO:0032689), negative regulation of toll-like receptor signaling pathway (GO:0034122), wound healing (GO:0042060), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), host-mediated modulation of intestinal microbiota composition (GO:0048874), regulation of inflammatory response (GO:0050727), positive regulation of inflammatory response (GO:0050729), defense response to Gram-positive bacterium (GO:0050830), protein homooligomerization (GO:0051260), defense response to virus (GO:0051607), regulation of mucus secretion (GO:0070255), necroptotic process (GO:0070266), pyroptotic inflammatory response (GO:0070269), negative regulation of ERK1 and ERK2 cascade (GO:0070373), neutrophil-mediated killing of gram-positive bacterium (GO:0070946), antiviral innate immune response (GO:0140374), NLRP6 inflammasome complex assembly (GO:0140739), positive regulation of interleukin-18-mediated signaling pathway (GO:2000494), immune system process (GO:0002376), inflammatory response (GO:0006954), signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186), protein secretion (GO:0009306), response to bacterium (GO:0009617), positive regulation of interleukin-1 beta production (GO:0032731), positive regulation of interleukin-18 production (GO:0032741), interleukin-18-mediated signaling pathway (GO:0035655), negative regulation of MAPK cascade (GO:0043409), innate immune response (GO:0045087), negative regulation of immune response (GO:0050777), protein maturation (GO:0051604), interleukin-1-mediated signaling pathway (GO:0070498)

GO Molecular Function (11): lipopolysaccharide binding (GO:0001530), double-stranded RNA binding (GO:0003725), vasopressin receptor activity (GO:0005000), ATP binding (GO:0005524), signaling adaptor activity (GO:0035591), pattern recognition receptor activity (GO:0038187), peptide binding (GO:0042277), lipoteichoic acid binding (GO:0070891), molecular condensate scaffold activity (GO:0140693), nucleotide binding (GO:0000166), signaling receptor activity (GO:0038023)

GO Cellular Component (9): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), nuclear membrane (GO:0031965), membraneless organelle (GO:0043228), canonical inflammasome complex (GO:0061702), NLRP6 inflammasome complex (GO:0140738), nucleus (GO:0005634), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
inflammatory response	4
cellular anatomical structure	3
inflammatory response to antigenic stimulus	2
carbohydrate derivative binding	2
protein-macromolecule adaptor activity	2
acute inflammatory response	1
regulation of inflammatory response to antigenic stimulus	1
negative regulation of inflammatory response	1
negative regulation of immune response	1
autophagy	1
regulation of catabolic process	1
negative regulation of cytokine production	1
type II interferon production	1
regulation of type II interferon production	1
toll-like receptor signaling pathway	1
negative regulation of immune system process	1
negative regulation of signal transduction	1
regulation of toll-like receptor signaling pathway	1
response to wounding	1
tissue regeneration	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
negative regulation of intracellular signal transduction	1
homeostasis of number of cells	1
host-mediated perturbation of symbiont process	1
regulation of defense response	1
regulation of response to external stimulus	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
regulation of inflammatory response	1
defense response to bacterium	1
protein complex oligomerization	1
defense response	1
response to virus	1
regulation of body fluid levels	1
regulation of secretion	1
regulation of multicellular organismal process	1
mucus secretion	1
programmed necrotic cell death	1
negative regulation of MAPK cascade	1

Protein interactions and networks

STRING

993 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NLRP6	NLRC4	Q9NPP4	998
NLRP6	AIM2	O14862	996
NLRP6	CASP1	P29466	994
NLRP6	NLRP7	Q8WX94	988
NLRP6	NLRP1	Q9C000	987
NLRP6	NLRP12	P59046	985
NLRP6	NLRP3	Q96P20	985
NLRP6	MEFV	O15553	966
NLRP6	PYCARD	Q9ULZ3	940
NLRP6	NAIP	Q13075	914
NLRP6	PYDC1	Q8WXC3	912
NLRP6	NLRP2	Q9NX02	903
NLRP6	MAVS	Q7Z434	868
NLRP6	IL18	Q14116	854
NLRP6	NLRC5	Q86WI3	851

IntAct

0 interactions, top by confidence:

BioGRID (446): TAB2 (Affinity Capture-Western), TAB3 (Affinity Capture-Western), TRIM38 (Affinity Capture-Western), NLRP6 (Reconstituted Complex), ESR2 (Affinity Capture-Western), PYCARD (Affinity Capture-Western), CASP1 (Affinity Capture-Western), ULK1 (Affinity Capture-Western), BECN1 (Affinity Capture-Western), ATG5 (Affinity Capture-Western), ATG12 (Affinity Capture-Western), ATG16L1 (Affinity Capture-Western), SQSTM1 (Affinity Capture-Western), PHB2 (Affinity Capture-Western), NLRP6 (Affinity Capture-Western)

ESM2 similar proteins: A1Z198, A6QLE5, B0FPE9, C3VPR6, D4A523, D9I2F9, D9I2G1, D9I2G3, D9I2G4, D9I2H0, E9Q5R7, O95521, P15533, P59044, P59045, P59046, P59047, Q0GKD5, Q288C4, Q2LKU9, Q2LKV2, Q2LKV5, Q2LKW6, Q3TKR3, Q5D7I6, Q5SWL7, Q5VWM6, Q63035, Q647I9, Q66X01, Q66X03, Q66X05, Q66X19, Q66X22, Q6B966, Q7RTR0, Q86W24, Q86W25, Q86W26, Q86W28

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

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	198
Likely benign	17
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1209857	GRCh37/hg19 13q12.2-12.3(chr13:28669064-31367407)x1	Likely pathogenic

SpliceAI

5257 predictions. Top by Δscore:

Variant	Effect	Δscore
11:279606:GC:G	donor_gain	1.0000
11:280062:C:CA	acceptor_gain	1.0000
11:280075:T:TA	acceptor_gain	1.0000
11:284621:G:T	donor_gain	1.0000
13:28174270:A:AG	acceptor_gain	1.0000
13:28174271:G:GA	acceptor_gain	1.0000
13:28174271:GTT:G	acceptor_gain	1.0000
13:28174359:G:GT	donor_gain	1.0000
13:28174394:G:GC	donor_loss	1.0000
13:28174395:T:A	donor_loss	1.0000
13:28176479:ATTTT:A	acceptor_loss	1.0000
13:28176487:TTTCA:T	acceptor_loss	1.0000
13:28176488:TTCA:T	acceptor_loss	1.0000
13:28176489:TCA:T	acceptor_loss	1.0000
13:28176490:CA:C	acceptor_loss	1.0000
13:28176491:A:AG	acceptor_gain	1.0000
13:28176492:G:GG	acceptor_gain	1.0000
13:28176492:GA:G	acceptor_gain	1.0000
13:28176492:GAGA:G	acceptor_gain	1.0000
13:28176492:GAGAA:G	acceptor_gain	1.0000
13:28176556:CATGG:C	donor_loss	1.0000
13:28176558:TGG:T	donor_loss	1.0000
13:28176560:G:GG	donor_gain	1.0000
13:28176560:GTAAG:G	donor_loss	1.0000
13:28176561:TAAGA:T	donor_loss	1.0000
13:28177859:TTTCA:T	acceptor_loss	1.0000
13:28177860:TTCA:T	acceptor_loss	1.0000
13:28177861:TCAGA:T	acceptor_loss	1.0000
13:28177862:CAG:C	acceptor_loss	1.0000
13:28177863:A:AC	acceptor_loss	1.0000

AlphaMissense

5685 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:280173:T:C	F147L	0.997
11:280175:C:A	F147L	0.997
11:280175:C:G	F147L	0.997
11:280780:T:C	F349S	0.995
11:280338:G:C	G202R	0.994
11:280360:C:T	T209I	0.994
11:280389:T:A	W219R	0.994
11:280389:T:C	W219R	0.994
11:280391:G:C	W219C	0.994
11:280391:G:T	W219C	0.994
11:280779:T:C	F349L	0.994
11:280781:C:A	F349L	0.994
11:280781:C:G	F349L	0.994
11:280358:G:C	K208N	0.993
11:280358:G:T	K208N	0.993
11:279407:T:C	F37S	0.992
11:280354:G:A	G207D	0.992
11:280897:C:A	P388H	0.992
11:280098:T:G	Y122D	0.991
11:280796:G:C	K354N	0.991
11:280796:G:T	K354N	0.991
11:280378:T:C	I215T	0.990
11:280387:A:T	D218V	0.990
11:280174:T:C	F147S	0.989
11:280357:A:T	K208M	0.989
11:280354:G:T	G207V	0.988
11:281370:T:C	F546L	0.988
11:281372:C:A	F546L	0.988
11:281372:C:G	F546L	0.988
11:280099:A:C	Y122S	0.987

dbSNP variants (sampled 300 via entrez): RS1000896712 (11:279818 C>A), RS1000905421 (11:279281 T>A,C,G), RS1001282161 (11:283515 G>A), RS1001339469 (11:284110 T>C), RS1001499895 (11:278705 C>T), RS1002211727 (11:277092 C>A,T), RS1002283346 (11:282277 G>A,C,T), RS1002642968 (11:283525 G>A), RS1002991440 (11:278320 G>T), RS1003008514 (11:283433 C>T), RS1003510006 (11:279233 C>T), RS1004217429 (11:279447 C>A,G), RS1004249773 (11:283174 G>T), RS1004595772 (11:279179 C>G,T), RS1005047523 (11:278984 C>T)

Disease associations

OMIM: gene MIM:609650 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST001335_19	Mean platelet volume	2.000000e-15
GCST001337_31	Platelet count	7.000000e-25
GCST002553_1	Pancreatic cancer	2.000000e-09
GCST003945_1	Hepcidin/transferrin saturation ratio	6.000000e-06
GCST003945_5	Hepcidin/transferrin saturation ratio	2.000000e-07
GCST004608_185	Granulocyte percentage of myeloid white cells	3.000000e-17
GCST004609_201	Monocyte percentage of white cells	4.000000e-25
GCST004625_134	Monocyte count	6.000000e-38
GCST005951_4	Body mass index	2.000000e-08
GCST006865_13	Bipolar disorder	6.000000e-06
GCST90002392_405	Mean corpuscular volume	5.000000e-12
GCST90002405_268	Reticulocyte count	4.000000e-09

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count
EFO:0007902	hepcidin:transferrin saturation ratio
EFO:0007997	granulocyte percentage of myeloid white cells
EFO:0007989	monocyte percentage of leukocytes
EFO:0005091	monocyte count
EFO:0004340	body mass index
EFO:0007986	reticulocyte count

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

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	increases expression, affects expression, increases abundance	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Particulate Matter	increases abundance, increases expression, decreases expression	2
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
di-n-butylphosphoric acid	affects expression	1
Acetaminophen	decreases expression	1
Cadmium	decreases expression	1
Estradiol	increases expression	1
N-Nitrosopyrrolidine	decreases expression	1
Ozone	affects expression, increases abundance	1
Silicon Dioxide	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	decreases expression	1

Clinical trials (associated diseases)

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