NOD2

Summary

NOD2 (nucleotide binding oligomerization domain containing 2, HGNC:5331) is a protein-coding gene on chromosome 16q12.1, encoding Nucleotide-binding oligomerization domain-containing protein 2 (Q9HC29). Pattern recognition receptor (PRR) that detects bacterial peptidoglycan fragments and other danger signals and plays an important role in gastrointestinal immunity.

This gene is a member of the Nod1/Apaf-1 family and encodes a protein with two caspase recruitment (CARD) domains and six leucine-rich repeats (LRRs). The protein is primarily expressed in the peripheral blood leukocytes. It plays a role in the immune response to intracellular bacterial lipopolysaccharides (LPS) by recognizing the muramyl dipeptide (MDP) derived from them and activating the NFKB protein. Mutations in this gene have been associated with Crohn disease and Blau syndrome. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.

Source: NCBI Gene 64127 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Blau syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 32
• Clinical variants (ClinVar): 1,203 total — 15 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 81
• Druggable target: yes — 6 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001370466

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5331
Approved symbol	NOD2
Name	nucleotide binding oligomerization domain containing 2
Location	16q12.1
Locus type	gene with protein product
Status	Approved
Aliases	BLAU, CD, PSORAS1, CLR16.3, NLRC2
Ensembl gene	ENSG00000167207
Ensembl biotype	protein_coding
OMIM	605956
Entrez	64127

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 8 protein_coding, 8 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000300589, ENST00000524712, ENST00000526417, ENST00000527052, ENST00000527070, ENST00000529633, ENST00000531674, ENST00000532206, ENST00000534057, ENST00000534067, ENST00000641284, ENST00000646677, ENST00000647318, ENST00000697425, ENST00000697426, ENST00000697427, ENST00000697428, ENST00000858093, ENST00000951248

RefSeq mRNA: 3 — MANE Select: NM_001370466 NM_001293557, NM_001370466, NM_022162

CCDS: CCDS10746, CCDS86525

Canonical transcript exons

ENST00000647318 — 12 exons

Exon	Start	End
ENSE00001110971	50729818	50729901
ENSE00001110972	50716587	50716670
ENSE00001110975	50725489	50725572
ENSE00001110977	50716891	50716974
ENSE00001110980	50723301	50723384
ENSE00001141601	50710558	50712373
ENSE00003638787	50722622	50722705
ENSE00003653572	50707855	50707960
ENSE00003692890	50719925	50720008
ENSE00003814259	50699488	50699954
ENSE00003819542	50731747	50733075
ENSE00003905954	50693606	50693662

Expression profiles

Bgee: expression breadth ubiquitous, 189 present calls, max score 91.90.

FANTOM5 (CAGE): breadth broad, TPM avg 2.3946 / max 114.4632, expressed in 343 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154030	2.1674	339
154031	0.1826	71
154032	0.0446	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	91.90	gold quality
mononuclear cell	CL:0000842	91.49	gold quality
leukocyte	CL:0000738	91.25	gold quality
cervix squamous epithelium	UBERON:0006922	90.66	silver quality
granulocyte	CL:0000094	90.11	gold quality
blood	UBERON:0000178	89.64	gold quality
lower esophagus mucosa	UBERON:0035834	87.82	gold quality
cervix epithelium	UBERON:0004801	87.51	silver quality
skin of leg	UBERON:0001511	84.30	gold quality
skin of abdomen	UBERON:0001416	83.10	gold quality
esophagus mucosa	UBERON:0002469	82.66	gold quality
mammalian vulva	UBERON:0000997	82.46	gold quality
zone of skin	UBERON:0000014	82.24	gold quality
penis	UBERON:0000989	82.20	gold quality
cartilage tissue	UBERON:0002418	81.62	gold quality
squamous epithelium	UBERON:0006914	80.12	gold quality
bone marrow cell	CL:0002092	79.85	gold quality
vagina	UBERON:0000996	79.70	gold quality
esophagus squamous epithelium	UBERON:0006920	79.13	gold quality
gingival epithelium	UBERON:0001949	78.33	silver quality
bone marrow	UBERON:0002371	78.14	gold quality
oviduct epithelium	UBERON:0004804	77.57	gold quality
epithelium of esophagus	UBERON:0001976	77.51	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.41	gold quality
gingiva	UBERON:0001828	77.20	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	74.71	gold quality
minor salivary gland	UBERON:0001830	74.27	gold quality
mouth mucosa	UBERON:0003729	74.17	gold quality
upper lobe of left lung	UBERON:0008952	74.13	gold quality
esophagus	UBERON:0001043	73.59	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.20

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): IFNG, IRF6, NFKB1, NFKB, NFKBIA, NR1I2, PTPN22, RELA, TNF

miRNA regulators (miRDB)

55 targeting NOD2, 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-6759-5P	99.99	66.54	785
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-4645-3P	99.76	69.33	993
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-3136-3P	99.57	66.59	781
HSA-MIR-7155-3P	99.57	66.48	794
HSA-MIR-516A-3P	99.46	67.96	1378
HSA-MIR-516B-3P	99.46	67.96	1378
HSA-MIR-7162-5P	99.46	68.08	1368
HSA-MIR-3140-5P	99.39	69.04	1136
HSA-MIR-302A-5P	99.39	68.21	1913
HSA-MIR-377-3P	99.37	70.18	1905
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-4796-5P	99.34	70.06	810
HSA-MIR-6808-5P	99.31	66.23	2150

Literature-anchored findings (GeneRIF, showing 40)

• Linkage of Inflammatory Bowel Disease to broad regions of chromosome 16 has been established by analysis of multiple populations. NOD2, located on proximal 16q, was recently identified as an IBD gene (PMID:11752413)
• Crohn’s disease is caused by mutations in the bacterial response protein NOD2. (PMID:11837220)
• CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease (PMID:11875755)
• nod2 protein on chromosome 16 is associated with Crohn’s disease (PMID:11890351)
• CARD15 genetic variation in a Quebec population: prevalence, genotype-phenotype relationship, and haplotype structure. (PMID:12019468)
• Lack of common NOD2 variants in Japanese patients with Crohn’s disease. (PMID:12105836)
• NOD2/CARD15 does not influence response to infliximab in Crohn’s disease. (PMID:12105838)
• Role of NOD2 variants in spondylarthritis. (PMID:12115195)
• NOD2 mutations in spondylarthropathy. (PMID:12115249)
• Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn’s disease. (PMID:12198692)
• Microsatellite study failed to identify NOD2 as a Crohn disease gene, despite presence of known disease alleles. (PMID:12210321)
• We conclude that the CARD15 mutation and hyporesponsive TLR4 allele do not contribute to ethnic variation in the incidence of PPROM. (PMID:12397216)
• Association of NOD2 genotype with clinical course of Crohn’s disease. (PMID:12454871)
• There is not a strong genetic association between CARD15 gene polymorphisms and psoriasis in the Italian population. (PMID:12459523)
• Familial cases of Crohn’s disease had a significantly higher frequency of the G908R variant than sporadic cases and a significantly higher proportion of homozygotes and compound heterozygotes. (PMID:12492195)
• R702W is not associated with susceptibility to Crohn’s disease in Ashkenazi Jews. The G908R, R702W, and L1007fsinsC variants share a common signaling defect in response to bacterial components. (PMID:12512038)
• Host recognition of bacterial muramyl dipeptide mediated through this protein, and this protein is implicated in susceptibility to Crohn’s disease (PMID:12514169)
• Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection (PMID:12527755)
• The three disease-associated SNPs were absent and there was no evidence of association between CARD15 and CD. Consequently, the disease-associated mutations in the Europeans, which are rare, have arisen recently (after the Asian-European split) (PMID:12529700)
• frameshift mutation in Crohn’s disease (PMID:12532667)
• CARD15/NOD2 risk alleles in the development of Crohn’s disease in the Australian population. (PMID:12556233)
• A haplotype in yhis gene confers a risk for Crohn disease in Ashkenazi Jews. (PMID:12577202)
• The insertion 3020insC mutation and the G2722C missense mutation in the CARD15 gene are not involved in susceptibility to ankylosing spondylitis. (PMID:12595906)
• The identification of the IBD1 gene on chromosome 16 as NOD-2 is unquestionably an important scientific discovery of the genetics of the inflammatory bowel diseases, Crohn’s disease and ulcerative colitis. (PMID:12617879)
• Presents genetic evidence for interaction of the 5q31 cytokine locus and this gene in Crohn disease. (PMID:12618963)
• alleles of a major susceptibility gene for Crohn disease (PMID:12626759)
• Although CARD15 3020insC appears to be etiologically important in Crohn’s disease, homozygous carriage does not always lead to inflammatory bowel disease. (PMID:12650796)
• CARD15/NOD2 is expressed in intestinal epithelial cells and may serve as a key component of innate mucosal responses to luminal bacteria as an antibacterial factor. (PMID:12671896)
• TNF-alpha(/IFN-gamma) treatment up-regulates the expression of the NOD2 gene in intestinal epithelial cells and this, with nod2 mutations, could be part of the complex pathophysiology of barrier disruption as it is observed in inflammatory bowel diseases. (PMID:12671897)
• This report confirms the importance of NOD2 as a susceptibility gene for Crohn’s Disease within the Irish population. (PMID:12673278)
• The NOD2 gene product is most abundant in Paneth cells in the terminal ileum, which could therefore play a critical and hitherto unrecognized role in the pathogenesis of NOD2-associated Crohn’s disease (PMID:12851870)
• Using a wide array of natural or modified muramyl peptides, it is shown that Nod1 and Nod2 have evolved divergent strategies to achieve peptidoglycan sensing (PMID:12871942)
• Crohn’s associated NOD2 gene variants are not involved in determining susceptibility to multiple sclerosis. (PMID:12876263)
• represents a pleiotropic autoimmune gene and is the first non-MHC gene to be associated with psoriatic arthritis (PMID:12879366)
• We conclude that germline mutations in the CARD15 gene are more frequently found in crohn’s disease. (PMID:12923865)
• a particular insertion mutation in the NOD2 gene does not appear to contribute to the genetic susceptibility of psoriasis in Crohn’s disease. (PMID:12930309)
• single nucleotide polymorphisms in the 3’-UTR were significantly increased only in Crohn’s disease patients without a variation in the CARD15 gene. (PMID:13680285)
• influence of mutations within the CARD15 protein gene on Crohn disease was more pronounced than that reported in any other study (PMID:14508222)
• A single amino acid change in NOD2 can lead to a chronic granulomatous uveitis. (PMID:14516815)
• Blau syndrome should be considered in the differential diagnosis of childhood uveitis. Genetic analysis of the CARD15/Nod2 gene is helpful in the diagnosis. (PMID:14522785)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	nod2	ENSDARG00000010756
mus_musculus	Nod2	ENSMUSG00000055994
rattus_norvegicus	Nod2	ENSRNOG00000014124

Paralogs (20): NLRP2 (ENSG00000022556), NLRP1 (ENSG00000091592), NOD1 (ENSG00000106100), NLRC5 (ENSG00000140853), NLRP12 (ENSG00000142405), NLRP14 (ENSG00000158077), NLRP4 (ENSG00000160505), NLRX1 (ENSG00000160703), NLRP3 (ENSG00000162711), 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

Nucleotide-binding oligomerization domain-containing protein 2 — Q9HC29 (reviewed: Q9HC29)

Alternative names: Caspase recruitment domain-containing protein 15, Inflammatory bowel disease protein 1

All UniProt accessions (7): A0A286YF65, A0A8V8TL25, Q9HC29, E9PK30, E9PLF7, H0YF53, J3QL80

UniProt curated annotations — full annotation on UniProt →

Function. Pattern recognition receptor (PRR) that detects bacterial peptidoglycan fragments and other danger signals and plays an important role in gastrointestinal immunity. Specifically activated by muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan found in every bacterial peptidoglycan type. NOD2 specifically recognizes and binds 6-O-phospho-MDP, the phosphorylated form of MDP, which is generated by NAGK. 6-O-phospho-MDP-binding triggers oligomerization that facilitates the binding and subsequent activation of the proximal adapter receptor-interacting RIPK2. Following recruitment, RIPK2 undergoes ‘Met-1’- (linear) and ‘Lys-63’-linked polyubiquitination by E3 ubiquitin-protein ligases XIAP, BIRC2, BIRC3 and the LUBAC complex, becoming a scaffolding protein for downstream effectors, triggering activation of the NF-kappa-B and MAP kinases signaling. This in turn leads to the transcriptional activation of hundreds of genes involved in immune response. Its ability to detect bacterial MDP plays a central role in maintaining the equilibrium between intestinal microbiota and host immune responses to control inflammation. An imbalance in this relationship results in dysbiosis, whereby pathogenic bacteria prevail on commensals, causing damage in the intestinal epithelial barrier as well as allowing bacterial invasion and inflammation. Acts as a regulator of appetite by sensing MDP in a subset of brain neurons: microbiota-derived MDP reach the brain, where they bind and activate NOD2 in inhibitory hypothalamic neurons, decreasing neuronal activity, thereby regulating satiety and body temperature. NOD2-dependent MDP-sensing of bacterial cell walls in the intestinal epithelial compartment contributes to sustained postnatal growth upon undernutrition. Also plays a role in antiviral response by acting as a sensor of single-stranded RNA (ssRNA) from viruses: upon ssRNA-binding, interacts with MAVS, leading to activation of interferon regulatory factor-3/IRF3 and expression of type I interferon. Also acts as a regulator of autophagy in dendritic cells via its interaction with ATG16L1, possibly by recruiting ATG16L1 at the site of bacterial entry. NOD2 activation in the small intestine crypt also contributes to intestinal stem cells survival and function: acts by promoting mitophagy via its association with ATG16L1. In addition to its main role in innate immunity, also regulates the adaptive immune system by acting as regulator of helper T-cell and regulatory T-cells (Tregs). Besides recognizing pathogens, also involved in the endoplasmic reticulum stress response: acts by sensing and binding to the cytosolic metabolite sphingosine-1-phosphate generated in response to endoplasmic reticulum stress, initiating an inflammation process that leads to activation of the NF-kappa-B and MAP kinases signaling. May also be involved in NLRP1 activation following activation by MDP, leading to CASP1 activation and IL1B release in macrophages. Acts as a pattern recognition receptor (PRR); able to activate NF-kappa-B. Can activate NF-kappa-B in a muramyl dipeptide (MDP)-independent manner.

Subunit / interactions. Homooligomer: homooligomerizes following muramyl dipeptide (MDP)-binding, promoting RIPK2 recruitment. Interacts (via CARD domain) with RIPK2 (via CARD domain). Following RIPK2 recruitment, RIPK2 homooligomerizes via its CARD domain and forms long filaments named RIPosomes. Interacts (via CARD domain) with ubiquitin; inhibiting interaction with RIPK2. Component of a signaling complex consisting of ARHGEF2, NOD2 and RIPK2. Interacts with ANKRD17 (via N-terminus). Interacts with HSPA1A; the interaction enhances NOD2 stability. Interacts (via both CARD domains) with HSP90; the interaction enhances NOD2 stability. Interacts (via CARD domain) with SOCS3; the interaction promotes NOD2 degradation. Interacts (via CARD domain) with ERBIN; the interaction inhibits activation of NOD2. Interacts with MAPKBP1; the interaction is enhanced in the presence of muramyl dipeptide (MDP) and inhibits NOD2 homooligomerization and activation. Interacts with INAVA; the interaction takes place upon Pattern recognition receptor (PRR) stimulation. Interacts (via NACHT domain) with CARD9. Interacts (via CARD domain) with CASP1; this interaction leads to IL1B processing. Also interacts with CASP4. Interacts with NLRP1; this interaction is enhanced in the presence of muramyl dipeptide (MDP) and leads to increased IL1B release. Interacts with NLRP12; this interaction promotes degradation of NOD2 through the ubiquitin-proteasome pathway. Interacts with ANKHD1, C10orf67, CHMP5, DOCK7, ENTR1, KRT15, LDOC1, PPP1R12C, PPP2R3B, TRIM41 and VIM. Interacts with MAVS; interaction takes place following single-stranded RNA (ssRNA)-binding. Interacts with ATG16L1. Interacts with IRGM; promoting IRGM ‘Lys-63’-linked polyubiquitination, which is required for interactions with the core autophagy factors.

Subcellular location. Cell membrane. Basolateral cell membrane. Cytoplasm. Mitochondrion Cytoplasm.

Tissue specificity. Expressed in monocytes, macrophages, dendritic cells, hepatocytes, preadipocytes, epithelial cells of oral cavity, lung and intestine, with higher expression in ileal Paneth cells and in intestinal stem cells. Expressed at higher level in leukocytes.

Post-translational modifications. Palmitoylated by ZDHHC5; palmitoylation is required for proper recruitment to the bacterial entry site and hence for proper signaling upon cognate peptidoglycan detection. Palmitoylation promotes localization to the cell membrane. Palmitoylation protects from SQSTM1/p62-dependent autophagic degradation. Polyubiquitinated by TRIM27, leading to proteasome-mediated degradation. Polyubiquitinated and degraded following muramyl dipeptide (MDP) stimulation, conferring MDP tolerance and preventing septic shock. Degraded via selective autophagy following interaction with IRGM. IRGM promotes NOD2-RIPK2 RIPosome recruitment to autophagosome membranes, promoting their SQSTM1/p62-dependent autophagic degradation. O-glycosylated by OGT, O-GlcNAcylation increases protein stability.

Disease relevance. Blau syndrome (BLAUS) [MIM:186580] An autosomal dominant inflammatory disorder characterized by the formation of immune granulomas invading the skin, joints and eye. Other organs may be involved. Clinical manifestations are variable and include early-onset granulomatous arthritis, uveitis and skin rash. Blindness, joint destruction and visceral involvement have been reported in severe cases. The disease is caused by variants affecting the gene represented in this entry. Inflammatory bowel disease 1 (IBD1) [MIM:266600] A chronic, relapsing inflammation of the gastrointestinal tract with a complex etiology. It is subdivided into Crohn disease and ulcerative colitis phenotypes. Crohn disease may affect any part of the gastrointestinal tract from the mouth to the anus, but most frequently it involves the terminal ileum and colon. Bowel inflammation is transmural and discontinuous; it may contain granulomas or be associated with intestinal or perianal fistulas. In contrast, in ulcerative colitis, the inflammation is continuous and limited to rectal and colonic mucosal layers; fistulas and granulomas are not observed. Both diseases include extraintestinal inflammation of the skin, eyes, or joints. Disease susceptibility is associated with variants affecting the gene represented in this entry. Yao syndrome (YAOS) [MIM:617321] An autoinflammatory disease characterized by periodic fever, dermatitis, polyarthritis, leg swelling, and gastrointestinal and sicca-like symptoms. YAOS is a complex disease with multifactorial inheritance. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Activity regulation. ADP-binding promotes an inactive closed conformation.

Domain organisation. The ATG16L1-binding motif mediates interaction with ATG16L1. Intramolecular interactions between the N-terminal moiety and the leucine-rich repeats (LRR) may be important for autoinhibition in the absence of activating signal. The LRR repeats recognize and bind muramyl dipeptide (MDP). The NACHT domain recognizes and binds sphingosine-1-phosphate in response to endoplasmic reticulum stress.

Induction. Up-regulated by muramyl-dipeptide and lipopolysaccharide.

Miscellaneous. Most abundant isoform.

Similarity. Belongs to the NOD1-NOD2 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9HC29-1	1, Nod2, NOD2L	yes
Q9HC29-2	2, Nod2b, NOD2S
Q9HC29-3	3, NOD2-C2

RefSeq proteins (3): NP_001280486, NP_001357395, NP_071445 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001315	CARD	Domain
IPR001611	Leu-rich_rpt	Repeat
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
IPR051261	NLR	Family

Pfam: PF00619, PF05729, PF13516, PF17776, PF17779

UniProt features (192 total): mutagenesis site 88, sequence variant 73, binding site 11, repeat 9, domain 3, splice variant 3, lipid moiety-binding region 2, chain 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HC29-F1	84.76	0.50

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 (11): 239; 252; 253; 299–306; 302; 303; 304; 305; 306; 307; 603

Post-translational modifications (2): 395, 1033

Mutagenesis-validated functional residues (88):

Position	Phenotype
31	abolished nf-kappa-b activation in response to muramyl dipeptide stimulation. decreased interaction with ripk2.
69	abolished nf-kappa-b activation in response to muramyl dipeptide stimulation.
91	abolished nf-kappa-b activation in response to muramyl dipeptide stimulation.
104	abolished binding to ubiquitin; when associated with r-200.
106	abolished nf-kappa-b activation in response to muramyl dipeptide stimulation. decreased interaction with ripk2.
145	dominant-negative mutant. abolished nf-kappa-b activation in response to muramyl dipeptide stimulation. decreased intera
152	does not affect nf-kappa-b activation in response to muramyl dipeptide stimulation.
177	abolished nf-kappa-b activation in response to muramyl dipeptide stimulation.
180	abolished nf-kappa-b activation in response to muramyl dipeptide stimulation.
200	abolished binding to ubiquitin; when associated with r-104.
232	abolished nf-kappa-b activation in response to muramyl dipeptide stimulation.
295	abolished nf-kappa-b activation in response to muramyl dipeptide stimulation.
305	no activation.
327	abolished nf-kappa-b activation in response to muramyl dipeptide stimulation.
333	abolished nf-kappa-b activation in response to muramyl dipeptide stimulation.
334	increased nf-kappa-b activation in response to muramyl dipeptide stimulation.
344	abolished nf-kappa-b activation in response to muramyl dipeptide stimulation.
379	no disruption in nod2-card9 interaction. decreased nf-kappa-b activation in response to muramyl dipeptide stimulation.
395	abolished palmitoylation and localization to the cell membrane; when associated with s-1033.
396	abolished nf-kappa-b activation in response to muramyl dipeptide stimulation.
401	abolished nf-kappa-b activation in response to muramyl dipeptide stimulation.
408	abolished nf-kappa-b activation in response to muramyl dipeptide stimulation.
426	does not affect nf-kappa-b activation in response to muramyl dipeptide stimulation.
429	abolished nf-kappa-b activation in response to muramyl dipeptide stimulation.
481	increased nf-kappa-b activation in response to muramyl dipeptide stimulation.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-168638	NOD1/2 Signaling Pathway
R-HSA-445989	TAK1-dependent IKK and NF-kappa-B activation
R-HSA-450302	activated TAK1 mediates p38 MAPK activation
R-HSA-450321	JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1
R-HSA-5689896	Ovarian tumor domain proteases
R-HSA-9020702	Interleukin-1 signaling
R-HSA-9705671	SARS-CoV-2 activates/modulates innate and adaptive immune responses

MSigDB gene sets: 579 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_DIGESTION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_AUTOPHAGY, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_NOD1_2_SIGNALING_PATHWAY, GOBP_REGULATION_OF_STRESS_ACTIVATED_PROTEIN_KINASE_SIGNALING_CASCADE, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_POSITIVE_REGULATION_OF_INTERLEUKIN_8_PRODUCTION, GOBP_REGULATION_OF_LEUKOCYTE_APOPTOTIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_B_CELL_ACTIVATION, REACTOME_NUCLEOTIDE_BINDING_DOMAIN_LEUCINE_RICH_REPEAT_CONTAINING_RECEPTOR_NLR_SIGNALING_PATHWAYS

GO Biological Process (57): temperature homeostasis (GO:0001659), pattern recognition receptor signaling pathway (GO:0002221), adaptive immune response (GO:0002250), positive regulation of dendritic cell antigen processing and presentation (GO:0002606), positive regulation of cytokine production involved in immune response (GO:0002720), positive regulation of dendritic cell cytokine production (GO:0002732), positive regulation of type 2 immune response (GO:0002830), autophagy (GO:0006914), defense response (GO:0006952), canonical NF-kappaB signal transduction (GO:0007249), response to nutrient (GO:0007584), detection of biotic stimulus (GO:0009595), detection of bacterium (GO:0016045), maintenance of gastrointestinal epithelium (GO:0030277), regulation of appetite (GO:0032098), response to muramyl dipeptide (GO:0032495), detection of muramyl dipeptide (GO:0032498), positive regulation of interleukin-1 beta production (GO:0032731), positive regulation of interleukin-10 production (GO:0032733), positive regulation of interleukin-17 production (GO:0032740), positive regulation of interleukin-6 production (GO:0032755), positive regulation of interleukin-8 production (GO:0032757), positive regulation of tumor necrosis factor production (GO:0032760), positive regulation of stress-activated MAPK cascade (GO:0032874), intracellular signal transduction (GO:0035556), intestinal stem cell homeostasis (GO:0036335), defense response to bacterium (GO:0042742), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), positive regulation of MAPK cascade (GO:0043410), innate immune response (GO:0045087), positive regulation of Notch signaling pathway (GO:0045747), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of JNK cascade (GO:0046330), positive regulation of gamma-delta T cell activation (GO:0046645), host-mediated modulation of intestinal microbiota composition (GO:0048874), positive regulation of epithelial cell proliferation (GO:0050679), regulation of inflammatory response (GO:0050727), positive regulation of B cell activation (GO:0050871), obsolete positive regulation of NF-kappaB transcription factor activity (GO:0051092), positive regulation of ERK1 and ERK2 cascade (GO:0070374)

GO Molecular Function (18): actin binding (GO:0003779), ATP binding (GO:0005524), enzyme binding (GO:0019899), protein kinase binding (GO:0019901), Hsp70 protein binding (GO:0030544), muramyl dipeptide binding (GO:0032500), pattern recognition receptor activity (GO:0038187), peptidoglycan binding (GO:0042834), ubiquitin binding (GO:0043130), ADP binding (GO:0043531), protein-containing complex binding (GO:0044877), CARD domain binding (GO:0050700), Hsp90 protein binding (GO:0051879), nucleotide binding (GO:0000166), GTPase activator activity (GO:0005096), protein binding (GO:0005515), anion binding (GO:0043168), carbohydrate derivative binding (GO:0097367)

GO Cellular Component (13): cytoplasm (GO:0005737), mitochondrion (GO:0005739), Golgi apparatus (GO:0005794), cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), cell surface (GO:0009986), basolateral plasma membrane (GO:0016323), extrinsic component of plasma membrane (GO:0019897), vesicle (GO:0031982), protein-containing complex (GO:0032991), phagocytic vesicle (GO:0045335), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
MAP kinase activation	2
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	1
Toll Like Receptor 3 (TLR3) Cascade	1
Interleukin-1 signaling	1
TRIF (TICAM1)-mediated TLR4 signaling	1
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	1
MyD88 cascade initiated on plasma membrane	1
Deubiquitination	1
Interleukin-1 family signaling	1
SARS-CoV-2-host interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
positive regulation of cytokine production	3
binding	3
cytoplasm	3
response to nutrient levels	2
adenyl ribonucleotide binding	2
heat shock protein binding	2
intracellular membrane-bounded organelle	2
multicellular organismal-level homeostasis	1
innate immune response-activating signaling pathway	1
immune response	1
dendritic cell antigen processing and presentation	1
positive regulation of antigen processing and presentation	1
regulation of dendritic cell antigen processing and presentation	1
cytokine production involved in immune response	1
positive regulation of production of molecular mediator of immune response	1
regulation of cytokine production involved in immune response	1
dendritic cell cytokine production	1
positive regulation of leukocyte mediated immunity	1
positive regulation of cytokine production involved in immune response	1
regulation of dendritic cell cytokine production	1
regulation of type 2 immune response	1
type 2 immune response	1
positive regulation of immune response	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
response to stress	1
intracellular signaling cassette	1
response to chemical	1
response to biotic stimulus	1
detection of stimulus	1
response to bacterium	1
detection of other organism	1
epithelial structure maintenance	1
digestive system process	1
regulation of biological quality	1
response to nitrogen compound	1
response to oxygen-containing compound	1
response to muramyl dipeptide	1

Protein interactions and networks

STRING

3199 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NOD2	RIPK2	O43353	999
NOD2	ATG16L1	Q676U5	999
NOD2	CARD9	Q9H257	990
NOD2	TLR2	O60603	976
NOD2	NLRP1	Q9C000	955
NOD2	MAVS	Q7Z434	952
NOD2	TLR9	Q9NR96	915
NOD2	IL23R	Q5VWK5	905
NOD2	ERBIN	Q96RT1	892
NOD2	DLG5	Q8TDM6	890
NOD2	NOD1	Q9Y239	883
NOD2	TLR4	O00206	883
NOD2	RIGI	O95786	876
NOD2	OAS2	P29728	871
NOD2	IRGM	A1A4Y4	861

IntAct

156 interactions, top by confidence:

A	B	Type	Score
XIAP	RIPK2	psi-mi:“MI:0914”(association)	0.950
NOD2	RIPK2	psi-mi:“MI:0915”(physical association)	0.870
RIPK2	NOD2	psi-mi:“MI:0915”(physical association)	0.870
RIPK2	NOD2	psi-mi:“MI:2364”(proximity)	0.870
NOD2	RIPK2	psi-mi:“MI:0914”(association)	0.870
NOD2	VIM	psi-mi:“MI:0915”(physical association)	0.850
NOD2	VIM	psi-mi:“MI:0403”(colocalization)	0.850
VIM	NOD2	psi-mi:“MI:0915”(physical association)	0.850
NOD2	VIM	psi-mi:“MI:0914”(association)	0.850
TEPSIN	AP4M1	psi-mi:“MI:0914”(association)	0.700
VCP	NOD2	psi-mi:“MI:0915”(physical association)	0.680
NOD2	VCP	psi-mi:“MI:0915”(physical association)	0.680
NOD2	ERBIN	psi-mi:“MI:0915”(physical association)	0.660

BioGRID (172): NOD2 (Affinity Capture-Western), ATG16L1 (Affinity Capture-Western), NOD2 (Affinity Capture-Western), NOD1 (Affinity Capture-Western), UBC (Co-crystal Structure), NOD2 (Affinity Capture-Western), IRGM (Affinity Capture-Western), IRGM (Reconstituted Complex), CYLD (Affinity Capture-Western), RNF31 (Affinity Capture-Western), RBCK1 (Affinity Capture-Western), RIPK2 (Affinity Capture-Western), SHARPIN (Affinity Capture-Western), TNFAIP3 (Affinity Capture-Western), SPATA2 (Affinity Capture-Western)

ESM2 similar proteins: A1IGU3, A1IGU4, A1IGU5, A2VDW6, A6QP75, A7E3N7, B2RUP2, C3VPR6, D3ZI76, Q0VCR8, Q14DK4, Q1LZ97, Q3MIN7, Q3TAA7, Q3UR97, Q4FZD7, Q53B87, Q53B88, Q5D0E6, Q60I26, Q60I27, Q61085, Q641Y9, Q69Z89, Q6NUI2, Q6P5Z2, Q6PFY1, Q6PJN8, Q70J99, Q86UR1, Q86VI1, Q86WN1, Q8BI71, Q8BTM9, Q8C0R7, Q8C190, Q8K045, Q8N1F8, Q8N9H8, Q8R5I4

Diamond homologs: G1T469, P10775, Q53B87, Q53B88, Q6E804, Q8BHB0, Q8K3Z0, Q9HC29, Q9Y239, P33076, C3VPR6, P59046

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
NOD2	“up-regulates activity”	RIPK2	binding
NOD2	up-regulates	Autophagy
NOD2	“up-regulates activity”	ATG16L1	binding
TNF	“up-regulates quantity by expression”	NOD2	“transcriptional regulation”
IFNG	“up-regulates quantity by expression”	NOD2	“transcriptional regulation”
NOD2	up-regulates	NfKb-p65/p50
HSP90AA1	“up-regulates quantity by stabilization”	NOD2	binding
HSP90AB1	“up-regulates quantity by stabilization”	NOD2	binding
HSPA1A	“up-regulates quantity by stabilization”	NOD2	binding
HSPA1B	“up-regulates quantity by stabilization”	NOD2	binding
“muramyl dipeptide”	“up-regulates activity”	NOD2	binding
NOD2	“up-regulates quantity by expression”	IRF4	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 48 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of autophagy	5	23.6×	3e-04
defense response to bacterium	6	14.7×	3e-04
positive regulation of canonical NF-kappaB signal transduction	7	11.6×	3e-04
cellular response to lipopolysaccharide	5	11.1×	3e-03
regulation of apoptotic process	5	9.5×	5e-03
defense response to virus	5	7.9×	8e-03
protein transport	6	6.0×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1203 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	3
Uncertain significance	635
Likely benign	313
Benign	28

Top pathogenic / likely-pathogenic (18)

Variant ID	HGVS	Classification
267317	NM_022162.2(NOD2):c.2446G>A	Pathogenic
267319	NM_022162.2(NOD2):c.2197G>T (p.Val733Leu)	Pathogenic
268134	NM_001370466.1(NOD2):c.964C>T (p.Leu322Phe)	Pathogenic
2921502	NM_001370466.1(NOD2):c.1068G>C (p.Glu356Asp)	Pathogenic
4279075	NM_001370466.1(NOD2):c.2344C>A (p.Gln782Lys)	Pathogenic
4694	NM_001370466.1(NOD2):c.920G>A (p.Arg307Gln)	Pathogenic
4695	NM_001370466.1(NOD2):c.1324C>T (p.Leu442Phe)	Pathogenic
4696	NM_001370466.1(NOD2):c.919C>T (p.Arg307Trp)	Pathogenic
4698	NM_001370466.1(NOD2):c.1406A>T (p.His469Leu)	Pathogenic
4699	NM_001370466.1(NOD2):c.1065C>G (p.Asp355Glu)	Pathogenic
4701	NM_001370466.1(NOD2):c.1066G>A (p.Glu356Lys)	Pathogenic
634817	NM_001370466.1(NOD2):c.1639C>T (p.Gln547Ter)	Pathogenic
97830	NM_001370466.1(NOD2):c.1361G>A (p.Gly454Asp)	Pathogenic
97832	NM_001370466.1(NOD2):c.1403G>A (p.Cys468Tyr)	Pathogenic
97842	NM_001370466.1(NOD2):c.1929C>A (p.Asn643Lys)	Pathogenic
1184615	NM_001370466.1(NOD2):c.1390A>C (p.Met464Leu)	Likely pathogenic
1694443	NM_001370466.1(NOD2):c.1345A>C (p.Thr449Pro)	Likely pathogenic
2921258	NM_001370466.1(NOD2):c.920G>T (p.Arg307Leu)	Likely pathogenic

SpliceAI

2045 predictions. Top by Δscore:

Variant	Effect	Δscore
16:50699483:CCCA:C	acceptor_loss	1.0000
16:50699484:CCAG:C	acceptor_loss	1.0000
16:50699486:A:AC	acceptor_loss	1.0000
16:50707852:TAGGC:T	acceptor_loss	1.0000
16:50707853:A:AG	acceptor_gain	1.0000
16:50707854:G:GG	acceptor_gain	1.0000
16:50707854:G:GT	acceptor_loss	1.0000
16:50707927:G:GT	donor_gain	1.0000
16:50707958:AAGG:A	donor_loss	1.0000
16:50707959:AGG:A	donor_loss	1.0000
16:50707962:T:G	donor_loss	1.0000
16:50712371:GTA:G	donor_gain	1.0000
16:50712374:G:GG	donor_gain	1.0000
16:50715127:T:G	donor_gain	1.0000
16:50716669:GC:G	donor_gain	1.0000
16:50719919:TTCCA:T	acceptor_loss	1.0000
16:50719920:TCCA:T	acceptor_loss	1.0000
16:50719921:CCAG:C	acceptor_loss	1.0000
16:50719922:CAG:C	acceptor_loss	1.0000
16:50719923:A:AC	acceptor_loss	1.0000
16:50719923:A:AG	acceptor_gain	1.0000
16:50719923:AGGCT:A	acceptor_gain	1.0000
16:50719924:G:C	acceptor_loss	1.0000
16:50719924:G:GG	acceptor_gain	1.0000
16:50719924:GGCT:G	acceptor_gain	1.0000
16:50719924:GGCTG:G	acceptor_gain	1.0000
16:50720007:GG:G	donor_gain	1.0000
16:50720008:GG:G	donor_gain	1.0000
16:50722702:TCAGG:T	donor_loss	1.0000
16:50722705:GGTAA:G	donor_loss	1.0000

AlphaMissense

6583 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:50711184:A:C	S425R	0.992
16:50711186:C:A	S425R	0.992
16:50711186:C:G	S425R	0.992
16:50710827:A:C	S306R	0.991
16:50710829:C:A	S306R	0.991
16:50710829:C:G	S306R	0.991
16:50719937:C:A	N881K	0.991
16:50719937:C:G	N881K	0.991
16:50711140:T:C	L410P	0.990
16:50716895:T:C	F851L	0.990
16:50716897:C:A	F851L	0.990
16:50716897:C:G	F851L	0.990
16:50710826:G:C	K305N	0.988
16:50710826:G:T	K305N	0.988
16:50711712:T:C	F601L	0.988
16:50711714:C:A	F601L	0.988
16:50711714:C:G	F601L	0.988
16:50710857:T:A	W316R	0.987
16:50710857:T:C	W316R	0.987
16:50712304:A:T	D798V	0.986
16:50723313:C:A	N937K	0.986
16:50723313:C:G	N937K	0.986
16:50725501:C:A	N965K	0.985
16:50725501:C:G	N965K	0.985
16:50710859:G:C	W316C	0.984
16:50710859:G:T	W316C	0.984
16:50711035:T:C	L375P	0.984
16:50722634:C:A	N909K	0.984
16:50722634:C:G	N909K	0.984
16:50711149:G:T	G413V	0.983

dbSNP variants (sampled 300 via entrez): RS1000110662 (16:50728557 A>C), RS1000113225 (16:50722822 G>A), RS1000357941 (16:50694527 C>T), RS1000396225 (16:50723221 G>A,C,T), RS1000524797 (16:50728930 T>C), RS1000547736 (16:50695312 C>T), RS1000630710 (16:50699294 C>A,G,T), RS1000799073 (16:50716940 C>A,G), RS1000932898 (16:50699534 G>A,C), RS1001139754 (16:50693715 C>T), RS1001222786 (16:50720276 T>A), RS1001237114 (16:50693537 A>G), RS1001277103 (16:50728576 T>C), RS1001389906 (16:50714837 C>G), RS1001412165 (16:50721734 C>T)

Disease associations

OMIM: gene MIM:605956 | disease phenotypes: MIM:186580, MIM:609464, MIM:266600, MIM:617321, MIM:607507, MIM:609888, MIM:109650, MIM:163950

GenCC curated gene-disease

Disease	Classification	Inheritance
Blau syndrome	Definitive	Autosomal dominant
inflammatory bowel disease 1	Limited	Unknown

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Blau syndrome	Definitive	AD

Mondo (9): Blau syndrome (MONDO:0008523), inflammatory bowel disease 1 (MONDO:0009960), Yao syndrome (MONDO:0015019), autoinflammatory syndrome (MONDO:0019751), psoriatic arthritis, susceptibility to (MONDO:0100232), leprosy, susceptibility to, 1 (MONDO:0012358), Behcet disease (MONDO:0007191), Noonan syndrome 1 (MONDO:0008104), Crohn disease (MONDO:0005011)

Orphanet (7): Blau syndrome (Orphanet:90340), Autoinflammatory syndrome (Orphanet:93665), Leprosy (Orphanet:548), Behçet disease (Orphanet:117), Noonan syndrome (Orphanet:648), Early-onset sarcoidosis (Orphanet:90341), NON RARE IN EUROPE: Crohn disease (Orphanet:206)

HPO phenotypes

81 total (30 of 81 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000112	Nephropathy
HP:0000155	Oral ulcer
HP:0000217	Xerostomia
HP:0000488	Retinopathy
HP:0000491	Keratitis
HP:0000501	Glaucoma
HP:0000518	Cataract
HP:0000554	Uveitis
HP:0000572	Visual loss
HP:0000585	Band keratopathy
HP:0000587	Abnormal optic nerve morphology
HP:0000598	Abnormality of the ear
HP:0000610	Abnormal choroid morphology
HP:0000613	Photophobia
HP:0000787	Nephrolithiasis
HP:0000822	Hypertension
HP:0000953	Hyperpigmentation of the skin
HP:0000958	Dry skin
HP:0000964	Eczematoid dermatitis
HP:0000988	Skin rash
HP:0001094	Iridocyclitis
HP:0001097	Keratoconjunctivitis sicca
HP:0001101	Iritis
HP:0001291	Abnormal cranial nerve morphology
HP:0001369	Arthritis
HP:0001376	Limitation of joint mobility
HP:0001386	Joint swelling
HP:0001392	Abnormality of the liver
HP:0001426	Non-Mendelian inheritance

GWAS associations

32 associations (top):

Study	Trait	p-value
GCST000008_1	Inflammatory bowel disease	5.000000e-10
GCST000014_3	Crohn’s disease	1.000000e-06
GCST000023_1	Crohn’s disease	7.000000e-14
GCST000042_10	Crohn’s disease	4.000000e-11
GCST000066_3	Crohn’s disease	1.000000e-21
GCST000071_3	Crohn’s disease	6.000000e-17
GCST000207_15	Crohn’s disease	3.000000e-24
GCST000225_2	Inflammatory bowel disease	4.000000e-10
GCST000546_3	Leprosy	4.000000e-40
GCST000705_2	Crohn’s disease	2.000000e-15
GCST000879_56	Crohn’s disease	4.000000e-69
GCST001438_12	Crohn’s disease	1.000000e-37
GCST001652_4	Crohn’s disease	3.000000e-10
GCST001729_21	Crohn’s disease	6.000000e-209
GCST002772_10	Leprosy	5.000000e-06
GCST002772_22	Leprosy	4.000000e-11
GCST002772_9	Leprosy	1.000000e-67
GCST003097_29	Pediatric autoimmune diseases	8.000000e-11
GCST003253_3	Microalbuminuria	9.000000e-07
GCST004009_13	Leprosy	5.000000e-08
GCST004131_18	Inflammatory bowel disease	1.000000e-38
GCST004132_6	Crohn’s disease	6.000000e-99
GCST005537_108	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	6.000000e-94
GCST005537_110	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	1.000000e-16
GCST005537_111	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	9.999889e-321
GCST007798_160	Asthma	6.000000e-09
GCST007800_28	Asthma (childhood onset)	1.000000e-10
GCST007932_54	Medication use (thyroid preparations)	2.000000e-08
GCST007995_1	Asthma (childhood onset)	4.000000e-08
GCST009325_23	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	2.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009933	Thyroid preparation use measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D001528	Behcet Syndrome	C07.465.075; C11.941.879.780.880.200; C14.907.940.100; C16.320.382.250; C17.800.827.368.250; C17.800.862.150
D003424	Crohn Disease	C06.405.205.731.500; C06.405.469.432.500
C538157	Blau syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1293266 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

6 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 670,240 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL428647	PACLITAXEL	4	332,542
CHEMBL92	DOCETAXEL ANHYDROUS	4	196,686
CHEMBL939	GEFITINIB	4	117,814
CHEMBL17205	CYCLOVALONE	2	348
CHEMBL1779325	MURAMYL DIPEPTIDE	1	22,395
CHEMBL49120	PD-0166285	1	455

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2066844	Efficacy	3	tacrolimus	Kidney Transplantation

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2066844	NOD2	3	0.75	1	tacrolimus
rs17221417	NOD2		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — NOD-like receptor family

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
ML130	Inhibition	4.7	pIC50

Binding affinities (BindingDB)

508 measured of 557 human assays (600 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
7-[(E)-but-2-enyl]-3-methyl-8-(3-phenylpropylsulfanyl)purine-2,6-dione	EC50	0.00868 nM
CHEMBL5180843	EC50	4.5 nM
MLS000079200	EC50	7.4 nM
CHEMBL5203244	EC50	44 nM
2,6-bis(fluoranyl)-N-pyridin-4-yl-benzamide	IC50	80 nM
MLS000056239	IC50	106 nM
1-[4-(diethylsulfamoyl)phenyl]-3-[3-(trifluoromethyl)phenyl]urea	IC50	123 nM
cid_44251464	IC50	146 nM
N-[1-(2,3-dimethylphenyl)-4,5,6,7-tetrahydroindazol-4-yl]-2,5-dimethyl-3-pyrazolecarboxamide	EC50	170 nM
7-(3-Methoxy-benzyl)-1,3-dimethyl-8-[(pyridin-3-ylmethyl)-amino]-3,7-dihydro-purine-2,6-dione	EC50	250 nM
SMR000415593	EC50	310 nM
cid_3390551	EC50	310 nM
MLS000100813	IC50	409 nM
sodium chloride	IC50	462 nM
cid_45253889	IC50	495 nM
MLS-0435754.0001	IC50	529 nM
MLS001159274	EC50	560 nM
SMR000653893	EC50	620 nM
2-methyl-1-(4-methylphenyl)sulfonyl-benzimidazole	IC50	700 nM	US-9320722: Regulators of aldehyde dehydrogenase ALDH3A1 and related therapeutic methods
SMR000523991	IC50	720 nM
SMR000652637	EC50	750 nM
N-[(4S)-1-(2-fluorophenyl)-4,5,6,7-tetrahydroindazol-4-yl]-2-methylpyrazole-3-carboxamide	IC50	781 nM
cid_353380	EC50	790 nM
ethyl 4-[[4-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)phenyl]carbonylamino]benzoate	EC50	850 nM
MLS-0425631.0001	IC50	891 nM
3-methyl-7-pentyl-8-(2-phenylethylsulfanyl)purine-2,6-dione	IC50	935 nM
cid_45253888	IC50	955 nM
MLS-0425704.0001	IC50	990 nM
cid_1106356	IC50	1030 nM
1-(3-methylphenyl)-3-[(Z)-(2-oxidanylidene-1-prop-2-enyl-indol-3-ylidene)amino]thiourea	EC50	1090 nM
cid_22583043	EC50	1100 nM
MLS-0425609.0001	IC50	1200 nM	US-9320722: Regulators of aldehyde dehydrogenase ALDH3A1 and related therapeutic methods
1-[3-(ethylthio)-1,2,4-thiadiazol-5-yl]-3-(3-fluorophenyl)urea	IC50	1220 nM
cid_814607	IC50	1220 nM
SMR000516584	IC50	1270 nM
MLS001174426	EC50	1300 nM
2-(1,3-benzothiazol-2-yl)-2-(5-chloranyl-1-ethyl-3-nitro-6-oxidanylidene-pyridazin-4-yl)ethanenitrile	EC50	1370 nM
MLS-0323733.0001	IC50	1470 nM
SMR000237723	EC50	1520 nM
cid_16017586	EC50	1560 nM
cid_2763795	EC50	1630 nM
SMR000274842	EC50	1650 nM
1-[2-methyl-5-[4-(4-nitrophenyl)piperazin-1-yl]sulfonyl-2,3-dihydroindol-1-yl]propan-1-one	EC50	1670 nM
SMR000591570	EC50	1690 nM
SMR000629937	EC50	1800 nM
1-heptylpyridin-4-imine;hydroiodide	IC50	1830 nM
4-(4-propan-2-ylphenyl)-2-(thiophen-2-ylcarbonylamino)thiophene-3-carboxylic acid	IC50	1840 nM
1-azepanyl-[5-(6-quinolinyloxymethyl)-3-isoxazolyl]methanone	EC50	1850 nM
5-(4-chlorophenyl)-N-[1-(2-fluorophenyl)-4,5,6,7-tetrahydroindazol-4-yl]-2-methyl-3-pyrazolecarboxamide	IC50	1920 nM
cid_20959045	EC50	2040 nM

ChEMBL bioactivities

420 potent at pChembl≥5 of 540 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	CHEMBL4781373
8.52	IC50	3	nM	CHEMBL4847211
8.40	IC50	4	nM	CHEMBL4514780
8.40	IC50	4	nM	CHEMBL4853179
8.35	EC50	4.5	nM	CHEMBL5180843
8.34	EC50	4.6	nM	CHEMBL6171851
8.30	IC50	5	nM	CHEMBL4870434
8.30	IC50	5	nM	CHEMBL4864576
8.05	IC50	9	nM	CHEMBL4858463
8.01	EC50	9.7	nM	CHEMBL6163668
8.00	EC50	9.9	nM	CHEMBL5070781
8.00	EC50	10	nM	CHEMBL1595790
7.93	EC50	11.7	nM	CHEMBL6171855
7.91	EC50	12.3	nM	CHEMBL6166662
7.89	IC50	13	nM	CHEMBL4514780
7.89	IC50	13	nM	CHEMBL4859716
7.85	IC50	14	nM	CHEMBL136244
7.82	IC50	15	nM	CHEMBL136106
7.80	IC50	16	nM	CHEMBL4799077
7.71	EC50	19.4	nM	CHEMBL6175777
7.70	IC50	20	nM	CHEMBL4861488
7.70	EC50	20.2	nM	CHEMBL6168569
7.70	EC50	20	nM	CHEMBL1351908
7.67	EC50	21.6	nM	CHEMBL6166357
7.66	IC50	22	nM	CHEMBL4864600
7.65	EC50	22.4	nM	CHEMBL6174639
7.61	EC50	24.8	nM	CHEMBL6167496
7.59	EC50	25.5	nM	CHEMBL6144443
7.59	EC50	25.8	nM	CHEMBL6169334
7.58	IC50	26	nM	CHEMBL4789724
7.52	IC50	30	nM	CHEMBL1713298
7.52	EC50	30	nM	CHEMBL5070781
7.51	EC50	30.6	nM	CHEMBL6174316
7.46	EC50	35	nM	CHEMBL5187281
7.43	IC50	37	nM	PD-0166285
7.41	EC50	39	nM	CHEMBL5077049
7.40	EC50	40	nM	CHEMBL5079672
7.40	EC50	40	nM	CHEMBL1468181
7.36	EC50	44	nM	CHEMBL5203244
7.35	EC50	45	nM	CHEMBL5079672
7.34	EC50	46	nM	MURAMYL DIPEPTIDE
7.34	EC50	46	nM	CHEMBL4090558
7.34	IC50	46	nM	CHEMBL4795976
7.34	IC50	46	nM	CHEMBL4793153
7.33	EC50	47	nM	CHEMBL5207301
7.31	EC50	49	nM	CHEMBL5086803
7.31	EC50	49	nM	CHEMBL4069541
7.28	IC50	53	nM	CHEMBL4776631
7.21	EC50	62	nM	CHEMBL5085864
7.21	EC50	61	nM	CHEMBL5193116

PubChem BioAssay actives

226 with measured affinity, of 1125 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-[5-[2-amino-5-(4-piperazin-1-ylphenyl)-3-pyridinyl]-2,3-dimethoxyphenyl]propane-1-sulfonamide	1739685: Inhibition of human NOD2 expressed in HEK293 cells coexpressing NFkappaB-SEAP reporter measured after 7 to 9 hrs by HEKBIue reporter assay	ic50	0.0010	uM
6-(2,6-dichlorophenyl)-2-[4-[2-(diethylamino)ethoxy]anilino]-8-(2-methylpropyl)pyrido[2,3-d]pyrimidin-7-one	1756907: Inhibition of human NOD2 expressed in HEK-blue cells coexpressing NFkappaB-SEAP reporter assessed as reduction in L18-MDP-induced NF-kappaB activation preincubated for 15 mins followed by L18-MDP stimulation and further incubated for 8 hrs by SEAP reporter gene assay	ic50	0.0030	uM
6-(2-chlorophenyl)-2-[4-[2-(diethylamino)ethoxy]anilino]-8-methylpyrido[2,3-d]pyrimidin-7-one	1756907: Inhibition of human NOD2 expressed in HEK-blue cells coexpressing NFkappaB-SEAP reporter assessed as reduction in L18-MDP-induced NF-kappaB activation preincubated for 15 mins followed by L18-MDP stimulation and further incubated for 8 hrs by SEAP reporter gene assay	ic50	0.0040	uM
2-[4-(1,3-benzothiazol-5-ylamino)-6-tert-butylsulfonylquinazolin-7-yl]oxyethanol	1569500: Inhibition of human NOD2 expressed in HEK293 cells assessed as reduction in MDP-induced IL8 production measured after 22 hrs by HTRF fluorescence assay	ic50	0.0040	uM
diethyl (2R)-2-[[(2S)-2-[[2-[[(E)-3-[4-[2-(1-adamantyl)acetyl]oxy-3-methoxyphenyl]prop-2-enoyl]amino]acetyl]amino]-3-methylbutanoyl]amino]pentanedioate	1871109: Agonist activity at human human NOD2 expressed in HEK-Blue NOD2 reporter cells by colorimetry based SEAP assay	ec50	0.0045	uM
2-[4-[2-(diethylamino)ethoxy]anilino]-6-(4-hydroxyphenyl)-8-methylpyrido[2,3-d]pyrimidin-7-one	1756907: Inhibition of human NOD2 expressed in HEK-blue cells coexpressing NFkappaB-SEAP reporter assessed as reduction in L18-MDP-induced NF-kappaB activation preincubated for 15 mins followed by L18-MDP stimulation and further incubated for 8 hrs by SEAP reporter gene assay	ic50	0.0050	uM
6-(2,6-dichlorophenyl)-2-[4-[2-(diethylamino)ethoxy]anilino]-8-[(3-methylsulfonylphenyl)methyl]pyrido[2,3-d]pyrimidin-7-one	1756907: Inhibition of human NOD2 expressed in HEK-blue cells coexpressing NFkappaB-SEAP reporter assessed as reduction in L18-MDP-induced NF-kappaB activation preincubated for 15 mins followed by L18-MDP stimulation and further incubated for 8 hrs by SEAP reporter gene assay	ic50	0.0050	uM
8-benzyl-6-(2,6-dichlorophenyl)-2-[4-[2-(diethylamino)ethoxy]anilino]pyrido[2,3-d]pyrimidin-7-one	1756907: Inhibition of human NOD2 expressed in HEK-blue cells coexpressing NFkappaB-SEAP reporter assessed as reduction in L18-MDP-induced NF-kappaB activation preincubated for 15 mins followed by L18-MDP stimulation and further incubated for 8 hrs by SEAP reporter gene assay	ic50	0.0090	uM
6-(2,6-dichlorophenyl)-2-[4-[2-(diethylamino)ethoxy]anilino]-8-(2-methoxyethyl)pyrido[2,3-d]pyrimidin-7-one	1756907: Inhibition of human NOD2 expressed in HEK-blue cells coexpressing NFkappaB-SEAP reporter assessed as reduction in L18-MDP-induced NF-kappaB activation preincubated for 15 mins followed by L18-MDP stimulation and further incubated for 8 hrs by SEAP reporter gene assay	ic50	0.0130	uM
2-[4-[2-(diethylamino)ethoxy]anilino]-8-methyl-6-phenylpyrido[2,3-d]pyrimidin-7-one	1756907: Inhibition of human NOD2 expressed in HEK-blue cells coexpressing NFkappaB-SEAP reporter assessed as reduction in L18-MDP-induced NF-kappaB activation preincubated for 15 mins followed by L18-MDP stimulation and further incubated for 8 hrs by SEAP reporter gene assay	ic50	0.0140	uM
2-[4-[2-(diethylamino)ethoxy]anilino]-8-ethyl-6-phenylpyrido[2,3-d]pyrimidin-7-one	1756907: Inhibition of human NOD2 expressed in HEK-blue cells coexpressing NFkappaB-SEAP reporter assessed as reduction in L18-MDP-induced NF-kappaB activation preincubated for 15 mins followed by L18-MDP stimulation and further incubated for 8 hrs by SEAP reporter gene assay	ic50	0.0150	uM
N-[5-[2-amino-5-(3-piperazin-1-ylphenyl)-3-pyridinyl]-3-fluoro-2-methoxyphenyl]propane-1-sulfonamide	1739685: Inhibition of human NOD2 expressed in HEK293 cells coexpressing NFkappaB-SEAP reporter measured after 7 to 9 hrs by HEKBIue reporter assay	ic50	0.0160	uM
6-(2-chlorophenyl)-8-methyl-2-(3-methylsulfonylanilino)pyrido[2,3-d]pyrimidin-7-one	1756907: Inhibition of human NOD2 expressed in HEK-blue cells coexpressing NFkappaB-SEAP reporter assessed as reduction in L18-MDP-induced NF-kappaB activation preincubated for 15 mins followed by L18-MDP stimulation and further incubated for 8 hrs by SEAP reporter gene assay	ic50	0.0200	uM
6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylsulfonylanilino)pyrido[2,3-d]pyrimidin-7-one	1756907: Inhibition of human NOD2 expressed in HEK-blue cells coexpressing NFkappaB-SEAP reporter assessed as reduction in L18-MDP-induced NF-kappaB activation preincubated for 15 mins followed by L18-MDP stimulation and further incubated for 8 hrs by SEAP reporter gene assay	ic50	0.0220	uM
N-[5-[2-amino-5-(4-piperazin-1-ylphenyl)-3-pyridinyl]-3-fluoro-2-methoxyphenyl]propane-1-sulfonamide	1739685: Inhibition of human NOD2 expressed in HEK293 cells coexpressing NFkappaB-SEAP reporter measured after 7 to 9 hrs by HEKBIue reporter assay	ic50	0.0260	uM
diethyl (2R)-2-[[(2S)-2-[[2-[[(E)-3-(4-dodecanoyloxy-3-methoxyphenyl)prop-2-enoyl]amino]acetyl]amino]-3-methylbutanoyl]amino]pentanedioate	1817382: Agonist activity at NOD2 in HEK-Blue hNOD2 cells assessed as increase in NFkappaB transactivation-mediated SEAP activity measured after 18 hrs by spectrophotometric method	ec50	0.0300	uM
4-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)-N-[4-(trifluoromethoxy)phenyl]benzamide	1178167: Inhibition of NOD2 (unknown origin) expressed in HEK293T cells coexpressing NF-kappaB driven luciferase reporter gene by HTS primary assay	ic50	0.0300	uM
dicyclopentyl (2R)-2-[[(2S)-3-methyl-2-[[2-[[(E)-3-(3-phenylphenyl)prop-2-enoyl]amino]acetyl]amino]butanoyl]amino]pentanedioate	1871109: Agonist activity at human human NOD2 expressed in HEK-Blue NOD2 reporter cells by colorimetry based SEAP assay	ec50	0.0350	uM
6-(2,6-dichlorophenyl)-2-[4-[2-(diethylamino)ethoxy]anilino]-8-methylpyrido[2,3-d]pyrimidin-7-one	1756907: Inhibition of human NOD2 expressed in HEK-blue cells coexpressing NFkappaB-SEAP reporter assessed as reduction in L18-MDP-induced NF-kappaB activation preincubated for 15 mins followed by L18-MDP stimulation and further incubated for 8 hrs by SEAP reporter gene assay	ic50	0.0370	uM
diethyl (2R)-2-[[(2S)-2-[[2-[[(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarbonyl]amino]acetyl]amino]-3-methylbutanoyl]amino]pentanedioate	1817382: Agonist activity at NOD2 in HEK-Blue hNOD2 cells assessed as increase in NFkappaB transactivation-mediated SEAP activity measured after 18 hrs by spectrophotometric method	ec50	0.0390	uM
dicyclopentyl (2R)-2-[[(2S)-2-[[2-[[(E)-3-(4-hydroxy-3-methoxyphenyl)prop-2-enoyl]amino]acetyl]amino]-3-methylbutanoyl]amino]pentanedioate	1817382: Agonist activity at NOD2 in HEK-Blue hNOD2 cells assessed as increase in NFkappaB transactivation-mediated SEAP activity measured after 18 hrs by spectrophotometric method	ec50	0.0400	uM
dicyclopentyl (2R)-2-[[(2S)-2-[[2-[[(E)-3-[4-[2-(1-adamantyl)acetyl]oxy-3-methoxyphenyl]prop-2-enoyl]amino]acetyl]amino]-3-methylbutanoyl]amino]pentanedioate	1871109: Agonist activity at human human NOD2 expressed in HEK-Blue NOD2 reporter cells by colorimetry based SEAP assay	ec50	0.0440	uM
N-[3-[2-amino-5-(4-piperazin-1-ylphenyl)-3-pyridinyl]-5-ethoxyphenyl]propane-2-sulfonamide	1739685: Inhibition of human NOD2 expressed in HEK293 cells coexpressing NFkappaB-SEAP reporter measured after 7 to 9 hrs by HEKBIue reporter assay	ic50	0.0460	uM
N-[5-[2-amino-5-(4-piperazin-1-ylphenyl)-3-pyridinyl]-3-chloro-2-methoxyphenyl]propane-1-sulfonamide	1739685: Inhibition of human NOD2 expressed in HEK293 cells coexpressing NFkappaB-SEAP reporter measured after 7 to 9 hrs by HEKBIue reporter assay	ic50	0.0460	uM
diethyl (2R)-2-[[(2S)-2-[[2-[[(E)-3-(4-hydroxy-3-methoxyphenyl)prop-2-enoyl]amino]acetyl]amino]-3-methylbutanoyl]amino]pentanedioate	1469591: Agonist activity at human NOD2 expressed in HEK-Blue cells assessed as induction of NF-kB transcriptional activity after 18 hrs by SEAP reporter gene assay	ec50	0.0460	uM
diethyl (2R)-2-[[(2S)-3-methyl-2-[[2-[[(E)-3-(3-phenylphenyl)prop-2-enoyl]amino]acetyl]amino]butanoyl]amino]pentanedioate	1871109: Agonist activity at human human NOD2 expressed in HEK-Blue NOD2 reporter cells by colorimetry based SEAP assay	ec50	0.0470	uM
diethyl (2R)-2-[[(2S)-2-[[2-[[2-(3,4-difluorophenyl)cyclopropanecarbonyl]amino]acetyl]amino]-3-methylbutanoyl]amino]pentanedioate	1817382: Agonist activity at NOD2 in HEK-Blue hNOD2 cells assessed as increase in NFkappaB transactivation-mediated SEAP activity measured after 18 hrs by spectrophotometric method	ec50	0.0490	uM
diethyl (2R)-2-[[(2S)-3-methyl-2-[[2-[[(E)-3-(4-nitrophenyl)prop-2-enoyl]amino]acetyl]amino]butanoyl]amino]pentanedioate	1817382: Agonist activity at NOD2 in HEK-Blue hNOD2 cells assessed as increase in NFkappaB transactivation-mediated SEAP activity measured after 18 hrs by spectrophotometric method	ec50	0.0490	uM
N-[3-[2-amino-5-(4-piperazin-1-ylphenyl)-3-pyridinyl]-5-methoxyphenyl]benzenesulfonamide	1739685: Inhibition of human NOD2 expressed in HEK293 cells coexpressing NFkappaB-SEAP reporter measured after 7 to 9 hrs by HEKBIue reporter assay	ic50	0.0530	uM
diethyl (2R)-2-[[(2S)-3-methyl-2-[[2-[[(E)-3-(3-phenoxyphenyl)prop-2-enoyl]amino]acetyl]amino]butanoyl]amino]pentanedioate	1871109: Agonist activity at human human NOD2 expressed in HEK-Blue NOD2 reporter cells by colorimetry based SEAP assay	ec50	0.0610	uM
diethyl (2R)-2-[[(2S)-2-[[2-[[(E)-3-(4-acetyloxy-3-methoxyphenyl)prop-2-enoyl]amino]acetyl]amino]-3-methylbutanoyl]amino]pentanedioate	1817382: Agonist activity at NOD2 in HEK-Blue hNOD2 cells assessed as increase in NFkappaB transactivation-mediated SEAP activity measured after 18 hrs by spectrophotometric method	ec50	0.0620	uM
dicyclopentyl (2R)-2-[[(2S)-2-[[2-[[(E)-3-(4-acetyloxy-3-methoxyphenyl)prop-2-enoyl]amino]acetyl]amino]-3-methylbutanoyl]amino]pentanedioate	1817382: Agonist activity at NOD2 in HEK-Blue hNOD2 cells assessed as increase in NFkappaB transactivation-mediated SEAP activity measured after 18 hrs by spectrophotometric method	ec50	0.0630	uM
diethyl (2R)-2-[[(2S)-2-[[2-[[(1S,2S)-2-(3,4-difluorophenyl)cyclopropanecarbonyl]amino]acetyl]amino]-3-methylbutanoyl]amino]pentanedioate	1817382: Agonist activity at NOD2 in HEK-Blue hNOD2 cells assessed as increase in NFkappaB transactivation-mediated SEAP activity measured after 18 hrs by spectrophotometric method	ec50	0.0660	uM
diethyl (2R)-2-[[(2S)-3-methyl-2-[[2-[[(E)-3-(4-propan-2-ylphenyl)prop-2-enoyl]amino]acetyl]amino]butanoyl]amino]pentanedioate	1817382: Agonist activity at NOD2 in HEK-Blue hNOD2 cells assessed as increase in NFkappaB transactivation-mediated SEAP activity measured after 18 hrs by spectrophotometric method	ec50	0.0710	uM
diethyl (2R)-2-[[(2S)-3-methyl-2-[[2-[[(E)-3-(3-nitrophenyl)prop-2-enoyl]amino]acetyl]amino]butanoyl]amino]pentanedioate	1871109: Agonist activity at human human NOD2 expressed in HEK-Blue NOD2 reporter cells by colorimetry based SEAP assay	ec50	0.0820	uM
6-(2,6-dichlorophenyl)-2-[4-[2-(diethylamino)ethoxy]anilino]-8-[(4-methylsulfonylphenyl)methyl]pyrido[2,3-d]pyrimidin-7-one	1756907: Inhibition of human NOD2 expressed in HEK-blue cells coexpressing NFkappaB-SEAP reporter assessed as reduction in L18-MDP-induced NF-kappaB activation preincubated for 15 mins followed by L18-MDP stimulation and further incubated for 8 hrs by SEAP reporter gene assay	ic50	0.0940	uM
diethyl (2R)-2-[[(2S)-2-[[2-[[(E)-3-[4-[6-[[4-[(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)methyl]benzoyl]amino]hexanoyloxy]-3-methoxyphenyl]prop-2-enoyl]amino]acetyl]amino]-3-methylbutanoyl]amino]pentanedioate	1848902: Agonist activity at NOD2 in HEK-Blue hNOD2 cells assessed as increase in NFkappaB activation incubated for 18 hrs by SEAP-based spectrophotometry analysis	ec50	0.1140	uM
N-[3-[2-amino-5-(4-piperazin-1-ylphenyl)-3-pyridinyl]-5-methoxyphenyl]propane-2-sulfonamide	1739685: Inhibition of human NOD2 expressed in HEK293 cells coexpressing NFkappaB-SEAP reporter measured after 7 to 9 hrs by HEKBIue reporter assay	ic50	0.1210	uM
diethyl (2R)-2-[[(2S)-2-[[2-[[(E)-3-(4-hydroxy-3-methoxyphenyl)prop-2-enoyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]pentanedioate	1469591: Agonist activity at human NOD2 expressed in HEK-Blue cells assessed as induction of NF-kB transcriptional activity after 18 hrs by SEAP reporter gene assay	ec50	0.1210	uM
N-[5-[2-amino-5-(4-piperazin-1-ylphenyl)-3-pyridinyl]-2-methoxy-3-methylphenyl]propane-1-sulfonamide	1739685: Inhibition of human NOD2 expressed in HEK293 cells coexpressing NFkappaB-SEAP reporter measured after 7 to 9 hrs by HEKBIue reporter assay	ic50	0.1290	uM
dicyclopentyl (2R)-2-[[(2S)-3-methyl-2-[[2-[[(E)-3-(3-phenoxyphenyl)prop-2-enoyl]amino]acetyl]amino]butanoyl]amino]pentanedioate	1871109: Agonist activity at human human NOD2 expressed in HEK-Blue NOD2 reporter cells by colorimetry based SEAP assay	ec50	0.1300	uM
diethyl (2R)-2-[[(2S)-2-[[2-[[(E)-3-(3-bromophenyl)prop-2-enoyl]amino]acetyl]amino]-3-methylbutanoyl]amino]pentanedioate	1871109: Agonist activity at human human NOD2 expressed in HEK-Blue NOD2 reporter cells by colorimetry based SEAP assay	ec50	0.1350	uM
6-(2,6-dichlorophenyl)-8-methyl-2-(4-methylsulfonylanilino)pyrido[2,3-d]pyrimidin-7-one	1756907: Inhibition of human NOD2 expressed in HEK-blue cells coexpressing NFkappaB-SEAP reporter assessed as reduction in L18-MDP-induced NF-kappaB activation preincubated for 15 mins followed by L18-MDP stimulation and further incubated for 8 hrs by SEAP reporter gene assay	ic50	0.1360	uM
6-(2,4-dichlorophenyl)-2-[4-[2-(diethylamino)ethoxy]anilino]-8-methylpyrido[2,3-d]pyrimidin-7-one	1756907: Inhibition of human NOD2 expressed in HEK-blue cells coexpressing NFkappaB-SEAP reporter assessed as reduction in L18-MDP-induced NF-kappaB activation preincubated for 15 mins followed by L18-MDP stimulation and further incubated for 8 hrs by SEAP reporter gene assay	ic50	0.1600	uM
diethyl (2R)-2-[[(2S)-2-[[2-[[(E)-3-(3,4-difluorophenyl)prop-2-enoyl]amino]acetyl]amino]-3-methylbutanoyl]amino]pentanedioate	1469591: Agonist activity at human NOD2 expressed in HEK-Blue cells assessed as induction of NF-kB transcriptional activity after 18 hrs by SEAP reporter gene assay	ec50	0.1720	uM
diethyl (2R)-2-[[(2S)-2-[[2-[[(E)-3-(3,4-difluorophenyl)prop-2-enoyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]pentanedioate	1469591: Agonist activity at human NOD2 expressed in HEK-Blue cells assessed as induction of NF-kB transcriptional activity after 18 hrs by SEAP reporter gene assay	ec50	0.1720	uM
(4R)-4-[[(2S)-2-[[(2R)-2-[(3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxypropanoyl]amino]propanoyl]amino]-5-amino-5-oxopentanoic acid	1524939: Binding affinity to human NOD2 LRR domain expressed in Escherichia coli by SPR assay	kd	0.2000	uM
cyclopropyl-[2-methyl-5-[4-(4-nitrophenyl)piperazin-1-yl]sulfonyl-2,3-dihydroindol-1-yl]methanone	1178167: Inhibition of NOD2 (unknown origin) expressed in HEK293T cells coexpressing NF-kappaB driven luciferase reporter gene by HTS primary assay	ic50	0.2000	uM
6-(2-chloro-4-fluorophenyl)-8-methyl-2-(3-methylsulfonylanilino)pyrido[2,3-d]pyrimidin-7-one	1756907: Inhibition of human NOD2 expressed in HEK-blue cells coexpressing NFkappaB-SEAP reporter assessed as reduction in L18-MDP-induced NF-kappaB activation preincubated for 15 mins followed by L18-MDP stimulation and further incubated for 8 hrs by SEAP reporter gene assay	ic50	0.2180	uM
diethyl (2R)-2-[[(2S)-3-methyl-2-[[2-[[(E)-3-phenylprop-2-enoyl]amino]acetyl]amino]butanoyl]amino]pentanedioate	1469591: Agonist activity at human NOD2 expressed in HEK-Blue cells assessed as induction of NF-kB transcriptional activity after 18 hrs by SEAP reporter gene assay	ec50	0.2230	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetylmuramyl-Alanyl-Isoglutamine	decreases reaction, affects activity, affects binding, increases expression, increases reaction (+6 more)	3
Lipopolysaccharides	affects cotreatment, increases expression, affects response to substance	2
Tobacco Smoke Pollution	decreases expression	2
GSK-J4	decreases expression	1
immune checkpoint inhibitor BMS-1	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
deoxynivalenol	affects reaction, affects binding, increases activity, increases expression, increases reaction (+4 more)	1
sulfolipid I	affects binding, decreases reaction	1
butyraldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
lauric acid	increases reaction, affects binding, decreases reaction	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
15-acetyldeoxynivalenol	affects binding, increases activity, increases expression, increases reaction	1
cordycepin	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
entinostat	increases expression	1
abrine	increases expression	1
(+)-JQ1 compound	decreases expression	1
Aripiprazole	affects cotreatment, increases expression	1
Anisomycin	affects binding, increases activity, increases expression, increases reaction	1
Arsenic	affects expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Cacodylic Acid	affects expression, increases abundance	1
Calcitriol	increases expression	1
Chloroquine	increases lipidation, affects reaction	1
Ciprofloxacin	decreases response to substance	1
Curcumin	affects binding, decreases reaction, increases reaction	1
Menthol	increases expression	1
Methapyrilene	increases methylation	1
Methotrexate	decreases expression	1

ChEMBL screening assays

126 unique, capped per target: 121 binding, 5 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1614247	Functional	PUBCHEM_BIOASSAY: uHTS luminescence assay for the identification of compounds that inhibit NOD2. (Class of assay: confirmatory) [Related pubchem assays (depositor defined):AID1575, AID1578, AID1579, AID1848, AID1849, AID1852, AID2001, AID22	PubChem BioAssay data set
CHEMBL1780350	Binding	Activation of NOD2 expressed in HEK293 cells assessed as increase in IL8 secretion measured at 0.01 to 0.7 uM after 18 hrs by ELISA	Synthesis of biotinylated muramyl tripeptides with NOD2-stimulating activity. — Bioorg Med Chem Lett

Cellosaurus cell lines

21 cell lines: 10 transformed cell line, 5 induced pluripotent stem cell, 5 cancer cell line, 1 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0406	MAIL8-3	Transformed cell line	Female
CVCL_A4IP	201B7-R334W	Induced pluripotent stem cell	Female
CVCL_A4IQ	Blau1-R334W-iPSC	Induced pluripotent stem cell	Male
CVCL_A4IR	Blau2-R334W-iPSC	Induced pluripotent stem cell	Male
CVCL_A4IS	Blau1-corrected-iPSC	Induced pluripotent stem cell	Male
CVCL_A4IT	Blau2-corrected-iPSC	Induced pluripotent stem cell	Male
CVCL_A7YR	HEK-Blue hNOD2	Transformed cell line	Female
CVCL_A7YX	293/hNOD2	Transformed cell line	Female
CVCL_A8GH	CLC12N2	Cancer cell line	Male
CVCL_A8GI	NUC12N2	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06660329	PHASE4	ENROLLING_BY_INVITATION	Efficacy and Safety of Tofacitinib in Refractory Blau Syndrome
NCT05879419	PHASE4	ACTIVE_NOT_RECRUITING	Recombinant Herpes Zoster Vaccine in Patients With Autoimmune Rheumatic Diseases
NCT00114465	PHASE4	COMPLETED	VSL#3 Versus Placebo in Maintenance of Remission in Crohn’s Disease
NCT00167882	PHASE4	COMPLETED	The Influence of 5-Aminosalicylates on Thiopurine Metabolite Levels
NCT00177866	PHASE4	TERMINATED	Safety of Celecoxib in Patients With Crohn’s Disease
NCT00225810	PHASE4	COMPLETED	A Study Comparing the Acceptability of Pentasa® Sachets Versus Pentasa® Tablets in Children With Crohn´s Disease
NCT00265772	PHASE4	UNKNOWN	Comparison of a Nutritional Anti-Inflammatory Treatment to Steroids for Pediatric Crohn’s Disease - the Molecular Basis
NCT00280956	PHASE4	COMPLETED	Open Label Natalizumab Safety Extension Study for Subjects With Crohn’s Disease
NCT00367705	PHASE4	UNKNOWN	VSL#3 Treatment in Children With Crohn’s Disease
NCT00462072	PHASE4	COMPLETED	Centocor Microarray Study of Patients
NCT00513552	PHASE4	WITHDRAWN	Treatment of Crohn’s Disease With an Antibiotic Regimen Directed Against Mycobacterium Avium Paratuberculosis
NCT00517296	PHASE4	COMPLETED	Endoscopic Ultrasound (EUS) Guided Treatment With Humira for Crohn’s Perianal Fistulas
NCT00546546	PHASE4	COMPLETED	Early Immunosuppressants in Crohn’s Disease
NCT00554710	PHASE4	COMPLETED	Top Down Versus Step Up Strategies in Crohn’s Disease
NCT00588653	PHASE4	COMPLETED	Diagnostic Accuracy of Capsule Endoscopy in Small Bowel Crohn’s Disease
NCT00609752	PHASE4	UNKNOWN	Adverse Effects of Glucocorticoid Therapy on Bone in Childhood Crohn’s Disease
NCT00672763	PHASE4	WITHDRAWN	Adjuvant Vitamin D With Corticosteroids in Active Crohn’s Disease
NCT00688636	PHASE4	COMPLETED	Infliximab for the Prevention of Recurrent Crohn’s Disease After Surgery
NCT00731809	PHASE4	UNKNOWN	Evaluation of PET CT in the Management of Patients With Crohn’s Disease.
NCT00752622	PHASE4	TERMINATED	Treatment With Infliximab in a Medical Setting (Study P05587)
NCT00801125	PHASE4	WITHDRAWN	Study of Tysabri (Natalizumab) in Patients Who Failed Anti-TNF-α Therapy
NCT00851565	PHASE4	UNKNOWN	Use of Combined Measurements of Serum Infliximab and Anti-infliximab Antibodies in the Treatment of Patients With Crohns Disease Failing Infliximab Therapy
NCT00972218	PHASE4	WITHDRAWN	Effectiveness and Safety of Spondylitis Related to Inflammatory Bowel Disease
NCT01024647	PHASE4	UNKNOWN	Optimizing Cimzia in Crohn’s Patients
NCT01030809	PHASE4	COMPLETED	Trial of a Treatment Algorithm for the Management of Crohn’s Disease
NCT01078935	PHASE4	UNKNOWN	The Effect of Probiotics on the Rate of Recovery of Inflammatory Bowel Disease Exacerbation, Endothelial Function, and Markers of Inflammation
NCT01181765	PHASE4	COMPLETED	The Efficacy of Open Label Infliximab for the Induction and Maintenance of Mucosal Healing in Small Bowel Crohn’s Disease Assessed Through Wireless Camera Endoscopy
NCT01183845	PHASE4	COMPLETED	Evaluation of the Applicability of the CDEIS to Data Obtained by the Colonic Capsule Endoscopy in Crohn Disease
NCT01215890	PHASE4	COMPLETED	Risedronate Therapy in the Treatment of Low Bone Mineral Density in Crohn’s Disease
NCT01235325	PHASE4	COMPLETED	The Effect of Vitamin K Supplementation on Bone Health in Adult Crohn’s Disease Patients
NCT01341808	PHASE4	COMPLETED	Immunogenicity of Hepatitis A Vaccine in Inflammatory Bowel Disease (IBD) Patients
NCT01346826	PHASE4	COMPLETED	Safety of Accelerated Infliximab Infusions in Patients With Inflammatory Bowel Disease (IBD)
NCT01369667	PHASE4	COMPLETED	Vitamin D Supplementation in Adult Crohn’s Disease
NCT01442025	PHASE4	COMPLETED	Study Investigating Tailored Treatment With Infliximab for Active Crohn’s Disease
NCT01505855	PHASE4	COMPLETED	Efficacy Study of Pneumococcal Vaccination in Crohn’s Disease
NCT01556672	PHASE4	COMPLETED	Adalimumab-psoriasis and Small Bowel Lesions
NCT01596894	PHASE4	COMPLETED	Azithromycin Based Therapy for Induction of Remission in Active Pediatric Crohn’s Disease
NCT01632462	PHASE4	UNKNOWN	A Prospective, Placebo Controlled, Double-Blind, Cross-over Study on the Effects of a Probiotic Preparation (VSL#3) on Metabolic Profile, Intestinal Permeability, Microbiota, Cytokines and Chemokines Expression and Other Inflammatory Markers in Pediatric Patients With Crohn’s Disease
NCT01696942	PHASE4	TERMINATED	Cimzia Versus Mesalamine for Crohn’s Recurrence
NCT01698307	PHASE4	COMPLETED	Enhanced Algorithm for Crohn’s Treatment Incorporating Early Combination Therapy