IFIH1

Summary

IFIH1 (interferon induced with helicase C domain 1, HGNC:18873) is a protein-coding gene on chromosome 2q24.2, encoding Interferon-induced helicase C domain-containing protein 1 (Q9BYX4). Innate immune receptor which acts as a cytoplasmic sensor of viral nucleic acids and plays a major role in sensing viral infection and in the activation of a cascade of antiviral responses including the induction of type I interferons and pro-inflammatory cytokines.

IFIH1 encodes MDA5 which is an intracellular sensor of viral RNA that triggers the innate immune response. Sensing RNA length and secondary structure, MDA5 binds dsRNA oligonucleotides with a modified DExD/H-box helicase core and a C-terminal domain, thus leading to a proinflammatory response that includes interferons. It has been shown that Coronaviruses (CoVs) as well as various other virus families, are capable of evading the MDA5-dependent interferon response, thus impeding the activation of the innate immune response to infection. MDA5 has also been shown to play an important role in enhancing natural killer cell function in malaria infection. In addition to its protective role in antiviral responses, MDA5 has been implicated in autoimmune and autoinflammatory diseases such as type 1 diabetes, systemic lupus erythematosus, and Aicardi-Goutieres syndrome

Source: NCBI Gene 64135 — RefSeq curated summary.

At a glance

• Gene–disease (curated): IFIH1-related type 1 interferonopathy (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 38
• Clinical variants (ClinVar): 1,758 total — 25 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 179
• Druggable target: yes
• MANE Select transcript: NM_022168

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18873
Approved symbol	IFIH1
Name	interferon induced with helicase C domain 1
Location	2q24.2
Locus type	gene with protein product
Status	Approved
Aliases	MDA-5, Hlcd, MDA5, IDDM19
Ensembl gene	ENSG00000115267
Ensembl biotype	protein_coding
OMIM	606951
Entrez	64135

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000421365, ENST00000464129, ENST00000648433, ENST00000649426, ENST00000649554, ENST00000649979, ENST00000679938, ENST00000697291

RefSeq mRNA: 1 — MANE Select: NM_022168 NM_022168

CCDS: CCDS2217

Canonical transcript exons

ENST00000649979 — 16 exons

Exon	Start	End
ENSE00001073455	162317855	162318684
ENSE00003970175	162267479	162267569
ENSE00003970176	162273795	162273944
ENSE00003970177	162276687	162276946
ENSE00003970179	162310765	162310933
ENSE00003970180	162268087	162268277
ENSE00003970181	162279996	162280112
ENSE00003970182	162306709	162306855
ENSE00003970183	162278205	162278328
ENSE00003970184	162267074	162267379
ENSE00003970185	162277415	162277693
ENSE00003970186	162282366	162282576
ENSE00003970187	162281328	162281545
ENSE00003970188	162288135	162288355
ENSE00003970189	162272226	162272387
ENSE00003970190	162293564	162293668

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 94.10.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.5467 / max 2135.6026, expressed in 1344 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
31557	21.2385	1330
31558	0.4335	179
31556	0.4218	87
31547	0.1514	57
31554	0.1444	25
31548	0.0852	34
31555	0.0634	19
31549	0.0085	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
palpebral conjunctiva	UBERON:0001812	94.10	gold quality
parotid gland	UBERON:0001831	93.71	gold quality
jejunal mucosa	UBERON:0000399	92.79	gold quality
monocyte	CL:0000576	91.62	gold quality
mononuclear cell	CL:0000842	91.29	gold quality
leukocyte	CL:0000738	91.08	gold quality
epithelium of nasopharynx	UBERON:0001951	90.45	gold quality
sperm	CL:0000019	89.88	gold quality
parietal pleura	UBERON:0002400	89.85	gold quality
visceral pleura	UBERON:0002401	89.82	gold quality
pleura	UBERON:0000977	89.63	gold quality
esophagus squamous epithelium	UBERON:0006920	89.12	gold quality
vermiform appendix	UBERON:0001154	88.21	gold quality
germinal epithelium of ovary	UBERON:0001304	87.90	gold quality
decidua	UBERON:0002450	87.26	gold quality
superficial temporal artery	UBERON:0001614	86.93	gold quality
squamous epithelium	UBERON:0006914	86.82	gold quality
male germ cell	CL:0000015	86.47	gold quality
duodenum	UBERON:0002114	86.44	gold quality
cervix squamous epithelium	UBERON:0006922	86.16	gold quality
tonsil	UBERON:0002372	86.15	gold quality
epithelium of esophagus	UBERON:0001976	86.10	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.08	gold quality
islet of Langerhans	UBERON:0000006	85.93	gold quality
granulocyte	CL:0000094	85.74	gold quality
calcaneal tendon	UBERON:0003701	85.74	gold quality
spleen	UBERON:0002106	85.67	gold quality
lymph node	UBERON:0000029	85.50	gold quality
caecum	UBERON:0001153	85.48	gold quality
bone marrow cell	CL:0002092	85.44	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-7052	yes	1122.66
E-MTAB-7037	yes	600.22
E-ANND-3	yes	7.71
E-MTAB-6379	no	241.85

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ERCC6

miRNA regulators (miRDB)

4 targeting IFIH1, 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-223-3P	99.99	70.14	1140
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-4277	98.34	67.17	1323
HSA-MIR-3137	97.26	66.78	761

Literature-anchored findings (GeneRIF, showing 40)

• mda-5: An interferon-inducible putative RNA helicase with double-stranded RNA-dependent ATPase activity and melanoma growth-suppressive properties (PMID:11805321)
• mda-5 is a novel type I IFN-inducible gene, which may contribute to apoptosis induction during terminal differentiation and during IFN treatment (PMID:14676839)
• mda-5 plays a central role in an intracellular signal transduction pathway that can lead to the activation of the IFN-beta promoter, and that the V proteins of paramyxoviruses interact with mda-5 to block its activity. (PMID:15563593)
• Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. (PMID:16116171)
• Rodent and human tumor cells containing constitutively activated Raf/Raf/MEK/ERK pathways were resistant to mda-5-induced killing. (PMID:16575407)
• report convincing statistical support for a sixth type 1 diabetes (T1D) locus in the innate immunity viral RNA receptor gene region IFIH1 (also known as mda-5 or Helicard) on chromosome 2q24.3 (PMID:16699517)
• results suggest that IFN-inducible mda-5 is involved in measles virus-induced expression of antiviral cytokines (PMID:16782388)
• In conclusion, our results show that in epithelial cells influenza A virus-induced antiviral cytokine gene expression is triggered by RIG-I and mda-5, whose expression is positively regulated by IFN-alpha. (PMID:16797201)
• beginning at 4 h postinfection, MDA-5 protein is degraded in poliovirus-infected cells; poliovirus-induced cleavage of MDA-5 may be a mechanism to antagonize production of type I interferon in response to viral infection (PMID:17267501)
• IFIH1 is upregulated in RA but that the A946T variant does not contribute significantly to the genetic background of RA (PMID:17442111)
• we confirm a significant contribution of the IFIH1 polymorphism to organ-specific autoimmune diseases, extending the range of conditions associated with this variant to include Graves’ disease (PMID:17535987)
• The putative dsRNA receptor MDA-5 may not play a pivotal role in the dsRNA-stimulated expression of inflammatory chemokines in airway epithelial cells. (PMID:17541283)
• An association of A946T polymorphism of the IFIH1 gene with the development of Graves’ disease in a Chinese population was not apparent. (PMID:18026693)
• The reported type 1 diabetes association is from a linkage disequilibrium region including three candidate genes, FAP, IFIH1 and GCA. (PMID:18071670)
• IFIH1 interferon induced helicase, GCA grancalcin or the potassium channel KCNH7 - are potential candidates implicated in the pathogenesis of multiple sclerosis. (PMID:18285833)
• Epidermal keratinocytes respond to viral double-stranded dsRNA equivalent poly(I:C) by expressing melanoma differentiation associated protein-5 (MDA-5) together with its signal pathway in an antiviral defense program targeting viral skin infections. (PMID:18684960)
• IFIH1 polymorphisms is associated with type 1 diabetes. (PMID:18927125)
• PIC-liposome could induce apoptosis and up-regulate cytoplasm receptors RIG-I and MDA5 in hepatoma cells (PMID:19154402)
• IFIH1-GCA-KCNH7 locus is not associated with genetic susceptibility to multiple sclerosis in French patients (PMID:19156166)
• gC1qR is a physiological inhibitor of the RIG-I and MDA5-mediated antiviral signaling pathway (PMID:19164550)
• MDA5, RIG-I, and LGP2 have roles in regulating signal transduction (PMID:19211564)
• study discovered 4 rare variants in IFIH1 that lowered type 1 diabetes risk independently of each other (odds ratio = 0.51 to 0.74; P = 1.3 x 10(-3) to 2.1 x 10(-16); variants are predicted to alter the expression and structure of IFIH1 (PMID:19264985)
• Identification of loss of function mutations in human genes encoding RIG-I and MDA5: implications for resistance to type I diabetes. (PMID:19324880)
• The V protein interaction was found to disrupt ATP hydrolysis mediated by both MDA5 and LGP2. (PMID:19403670)
• association between two non-synonymous SNPs (rs1990760 and rs3747517) in the IFIH1 gene and multiple sclerosis in a large group of Danish patients. (PMID:19450885)
• the structural basis of dsRNA recognition by MDA5 protein (PMID:19531363)
• no association of genetic polymorphism with type i diabetes in the Belgian population (PMID:19539001)
• RNA helicase encoded by MDA-5 is a critical molecule involved in innate immune defense against viruses. Viral infection may play a role in the pathogenesis of clinically amyopathic dermatomyositis and rapidly progressive interstitial lung disease. (PMID:19565506)
• This review summarizes the discovery of cytoplasmic sensor MDA-5, how it recognizes nucleic acids, its signaling pathways leading to cytokine synthesis, and viral countermeasures that have evolved to antagonize MDA-5 function. (PMID:19615405)
• Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon-independent apoptosis in human melanoma cells. (PMID:19620789)
• Genetic polymorphism in IFIH1 gene does not confer susceptibility to autoimmune thyroid disease in the Japanese population. (PMID:19742420)
• Data show that found that IFIH1, a susceptibility gene of type 1 diabetes, interacts with YES1, which plays a role in glucose transport. (PMID:19797678)
• An association between the Ala946Thr polymorphism of IFIH1 and type 1 diabetes susceptibility has been detected in European populations. (PMID:19841890)
• RIG-I and MDA5 both contribute to the recognition of MV and the V protein promotes MV growth at least partly by inhibiting the MDA5-mediated IFN responses (PMID:19846522)
• TLR3 and MDA5, but not RIG-I, are required for maximal sensing of rhinovirus dsRNA and that TLR3 and MDA5 signal through a common downstream signaling intermediate, IRF3. (PMID:19890046)
• our data suggest no contribution from IFIH1 rs1990760 polymorphism to the pathogenesis of either Graves’ disease, Hashimoto’s thyroiditis or Addison’s disease in our study populations (PMID:19961590)
• This study shows that the nsSNP rs35667974/Ile923Val does not have a role in susceptibility to MS. (PMID:20116863)
• The IFIH1 Ala946Thr polymorphism was not associated with susceptibility to systemic lupus erythematosus or dermatomyositis. (PMID:20467774)
• These findings suggest that variants in IFIH1 confer different susceptibility to diverse viral infections. (PMID:20538742)
• The mechanism of the association of the nsSNP with T1D remains to be determined, but does not involve IFIH1 mRNA modulation (PMID:20644636)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ifih1	ENSDARG00000018553
mus_musculus	Ifih1	ENSMUSG00000026896
rattus_norvegicus	Ifih1	ENSRNOG00000006227
caenorhabditis_elegans	drh-3	WBGENE00008400

Paralogs (2): RIGI (ENSG00000107201), DHX58 (ENSG00000108771)

Protein

Protein identifiers

Interferon-induced helicase C domain-containing protein 1 — Q9BYX4 (reviewed: Q9BYX4)

Alternative names: Clinically amyopathic dermatomyositis autoantigen 140 kDa, Helicase with 2 CARD domains, Interferon-induced with helicase C domain protein 1, Melanoma differentiation-associated protein 5, Murabutide down-regulated protein, RIG-I-like receptor 2, RNA helicase-DEAD box protein 116

All UniProt accessions (4): A0A3B3IRK8, A0A7P0Z4A9, A0A8V8TKX2, Q9BYX4

UniProt curated annotations — full annotation on UniProt →

Function. Innate immune receptor which acts as a cytoplasmic sensor of viral nucleic acids and plays a major role in sensing viral infection and in the activation of a cascade of antiviral responses including the induction of type I interferons and pro-inflammatory cytokines. Its ligands include mRNA lacking 2’-O-methylation at their 5’ cap and long-dsRNA (>1 kb in length). Upon ligand binding it associates with mitochondria antiviral signaling protein (MAVS/IPS1) which activates the IKK-related kinases: TBK1 and IKBKE which phosphorylate interferon regulatory factors: IRF3 and IRF7 which in turn activate transcription of antiviral immunological genes, including interferons (IFNs); IFN-alpha and IFN-beta. Responsible for detecting the Picornaviridae family members such as encephalomyocarditis virus (EMCV), mengo encephalomyocarditis virus (ENMG), and rhinovirus. Detects coronavirus SARS-CoV-2. Can also detect other viruses such as dengue virus (DENV), west Nile virus (WNV), and reovirus. Also involved in antiviral signaling in response to viruses containing a dsDNA genome, such as vaccinia virus. Plays an important role in amplifying innate immune signaling through recognition of RNA metabolites that are produced during virus infection by ribonuclease L (RNase L). May play an important role in enhancing natural killer cell function and may be involved in growth inhibition and apoptosis in several tumor cell lines.

Subunit / interactions. Monomer in the absence of ligands and homodimerizes in the presence of dsRNA ligands. Can assemble into helical or linear polymeric filaments on long dsRNA. Interacts with MAVS/IPS1. Interacts (via the CARD domains) with TKFC, the interaction is inhibited by viral infection. Interacts with PCBP2. Interacts with NLRC5. Interacts with PIAS2-beta. Interacts with DDX60. Interacts with ANKRD17. Interacts with IKBKE. Interacts with ATG5 and ATG12, either as ATG5 and ATG12 monomers or as ATG12-ATG5 conjugates. Interacts with ZCCHC3; leading to activate IFIH1/MDA5. Interacts with RNF123. Interacts with DDX3X. Interacts with NOD1; this interaction promotes transcription of antiviral genes and inhibition of viral replication. Interacts with ECSIT; this interaction bridges IFIH1 to the MAVS complex at the mitochondrion. (Microbial infection) Interacts with V protein of paramyxoviruses; these interactions prevent IFN-beta induction, and subsequent establishment of an antiviral state. (Microbial infection) Interacts with herpes simplex virus 1 protein US11; this interaction prevents the interaction of MAVS/IPS1 to IFIH1. (Microbial infection) Interacts with Encephalomyocarditis virus protein 2C; this interaction inhibits the induction of the IFN-beta signal pathway. (Microbial infection) Interacts with protease 3C of coxsackievirus A16; this interaction inhibits IFIH1 thereby attenuating type-I IFN production. (Microbial infection) Interacts with SARS-COV-2 virus protein NSP3; the interaction antagonizes ISG15-dependent IFIH1 activation via active de-ISGylation. (Microbial infection) Interacts with measles V protein; this interaction is involved in the inhibition of the host type I interferon signaling pathway by the virus.

Subcellular location. Cytoplasm. Nucleus. Mitochondrion.

Tissue specificity. Widely expressed, at a low level. Expression is detected at slightly highest levels in placenta, pancreas and spleen and at barely levels in detectable brain, testis and lung.

Post-translational modifications. Sumoylated. Sumoylation positively regulates its role in type I interferon induction and is enhanced by PIAS2-beta. Ubiquitinated by RNF125, leading to its degradation by the proteasome. USP17/UPS17L2-dependent deubiquitination positively regulates the receptor. Ubiquitinated by TRIM25 via ‘Lys-63’-linked ubiquitination, promoting activation of IFIH1/MDA5. Ubiquitinated by TRIM40 via ‘Lys-48’-linked ubiquitination; leading to proteasomal degradation. Ubiquitinated by TRIM65 via ‘Lys-63’-linked ubiquitination, promoting activation of IFIH1/MDA5. ISGylated by ISG15. ISGylation increases upon infection with dengue (DENV) or Zika (ZIKV) viruses. ISGylation at Lys-23 and Lys-43 is dependent of dephosphorylation at Ser-88, regulates mitochondrial translocation and oligomerization. Essential for IFIH1/MDA5-mediated cytokine responses and restriction of virus replication. Phosphorylated at Ser-88. Dephosphorylated by phosphatases PPP11CA/PPP11CC; dephosphorylation precedes and is required for ISGylation. During apoptosis, processed into 3 cleavage products. The helicase-containing fragment, once liberated from the CARD domains, translocate from the cytoplasm to the nucleus. The processed protein significantly sensitizes cells to DNA degradation. (Microbial infection) Cleaved and inactivated by the protease 2A of coxsackievirus B3, poliovirus and enterovirus 71 allowing the virus to disrupt the host type I interferon production.

Disease relevance. Type 1 diabetes mellitus 19 (T1D19) [MIM:610155] A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical features are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. Disease susceptibility may be associated with variants affecting the gene represented in this entry. IFIH1 is the CADM-140 autoantigen, involved in clinically amyopathic dermatomyositis (CADM). This is a chronic inflammatory disorder that shows typical skin manifestations of dermatomyositis but has no or little evidence of clinical myositis. Anti-CADM-140 antibodies appear to be specific to dermatomyositis, especially CADM. Patients with anti-CADM-140 antibodies frequently develop life-threatening acute progressive interstitial lung disease (ILD). Aicardi-Goutieres syndrome 7 (AGS7) [MIM:615846] A form of Aicardi-Goutieres syndrome, a genetically heterogeneous disease characterized by cerebral atrophy, leukoencephalopathy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon, and negative serologic investigations for common prenatal infection. Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. Severe neurological dysfunctions manifest in infancy as progressive microcephaly, spasticity, dystonic posturing and profound psychomotor retardation. Death often occurs in early childhood. The disease is caused by variants affecting the gene represented in this entry. Singleton-Merten syndrome 1 (SGMRT1) [MIM:182250] An autosomal dominant disorder with variable expression. Core features are marked aortic calcification, dental anomalies, osteopenia, acro-osteolysis, and to a lesser extent glaucoma, psoriasis, muscle weakness, and joint laxity. Dental anomalies include delayed eruption and immature root formation of anterior permanent teeth, early loss of permanent teeth due to short roots, acute root resorption, high caries, and aggressive alveolar bone loss. Additional clinical manifestations include particular facial characteristics and abnormal joint and muscle ligaments. The disease is caused by variants affecting the gene represented in this entry. Immunodeficiency 95 (IMD95) [MIM:619773] An autosomal recessive disorder characterized by the onset of recurrent and severe viral respiratory infections in infancy or early childhood, and impaired interferon production during viral infection. The disease is caused by variants affecting the gene represented in this entry.

Induction. By interferon (IFN) and TNF.

Miscellaneous. In HIV-1 infected HeLa-CD4 cells, overexpression of IFIH1 results in a great increase in the level of secreted viral p24 protein.

Similarity. Belongs to the helicase family. RLR subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BYX4-1	1	yes
Q9BYX4-2	2

RefSeq proteins (1): NP_071451* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001650	Helicase_C-like	Domain
IPR006935	Helicase/UvrB_N	Domain
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR014001	Helicase_ATP-bd	Domain
IPR021673	RLR_CTR	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR031964	CARD_dom	Domain
IPR038557	RLR_C_sf	Homologous_superfamily
IPR041204	RIG-I-like_C	Domain
IPR051363	RLR_Helicase	Family

Pfam: PF00271, PF04851, PF11648, PF16739, PF18119

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (119 total): helix 28, mutagenesis site 19, strand 17, sequence variant 14, turn 8, modified residue 6, sequence conflict 6, domain 5, binding site 4, site 3, cross-link 2, splice variant 2, region of interest 2, compositionally biased region 2, chain 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
3GA3	X-RAY DIFFRACTION	1.45
3B6E	X-RAY DIFFRACTION	1.6
9LOV	ELECTRON MICROSCOPY	3.07
7DNI	ELECTRON MICROSCOPY	3.2
7DNJ	ELECTRON MICROSCOPY	3.3
4GL2	X-RAY DIFFRACTION	3.56
7JL0	ELECTRON MICROSCOPY	4.3
7JL2	ELECTRON MICROSCOPY	4.3
2RQB	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BYX4-F1	80.16	0.44

Functional residue map

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

Catalytic / active sites (3): 208–209 (cleavage); 216–217 (cleavage); 251–252 (cleavage)

Ligand- & substrate-binding residues (4): 907; 910; 962; 964

Post-translational modifications (8): 88, 289, 291, 301, 645, 828, 23, 43

Mutagenesis-validated functional residues (19):

Position	Phenotype
23	loss of isgylation, loss of oligomerization, strongly reduced signaling activity and ifnb induction, loss of virus repli
43	loss of isgylation, loss of oligomerization, strongly reduced signaling activity and ifnb induction, loss of virus repli
68	no effect on isgylation or signaling activity and ifnb induction.
74–75	loss of oligomerization.
88	increases isgylation. no effect on signaling activity and ifnb induction.
88	loss of signaling activity and ifnb induction. reduced isgylation. loss of virus replication restriction.
88	no effect on signaling activity and ifnb induction.
251	no cleavage and no acceleration of dna degradation.
335	loss of dsrna-induced atpase activity. no effect on rna binding. changed mda-5 signaling pathway.
443–446	loss of dsrna-induced atpase activity. no effect on rna binding. changed mda-5 signaling pathway.
444	no acceleration of dna degradation, no binding to atp, and no helicase activity.
488–490	loss of dsrna-induced atpase activity. no effect on rna binding. changed mda-5 signaling pathway.
789–793	loss of dsrna-induced atpase activity. loss of mda-5 signaling pathway.
818–822	loss of dsrna-induced atpase activity. no effect on mda-5 signaling pathway.
828	promotes multimerization after polyi:c stimulation; greatly enhances signaling.
828	inhibits multimerization after polyi:c stimulation.
829	moderately increases signaling.
841–842	loss of oligomerization.
848–849	loss of oligomerization.

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-168928	DDX58/IFIH1-mediated induction of interferon-alpha/beta
R-HSA-5689880	Ub-specific processing proteases
R-HSA-5689896	Ovarian tumor domain proteases
R-HSA-918233	TRAF3-dependent IRF activation pathway
R-HSA-933541	TRAF6 mediated IRF7 activation
R-HSA-933542	TRAF6 mediated NF-kB activation
R-HSA-933543	NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10
R-HSA-936440	Negative regulators of DDX58/IFIH1 signaling
R-HSA-9692916	SARS-CoV-1 activates/modulates innate immune responses
R-HSA-9705671	SARS-CoV-2 activates/modulates innate and adaptive immune responses
R-HSA-9833109	Evasion by RSV of host interferon responses
R-HSA-9909505	Modulation of host responses by IFN-stimulated genes
R-HSA-9920588	Dengue virus activates/modulates innate and adaptive immune responses

MSigDB gene sets: 860 (showing top): REACTOME_DDX58_IFIH1_MEDIATED_INDUCTION_OF_INTERFERON_ALPHA_BETA, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_CELLULAR_RESPONSE_TO_VIRUS, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_NEGATIVE_REGULATION_OF_VIRAL_PROCESS, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_RESPONSE_TO_TYPE_I_INTERFERON, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_POSITIVE_REGULATION_OF_TUMOR_NECROSIS_FACTOR_SUPERFAMILY_CYTOKINE_PRODUCTION

GO Biological Process (22): cytoplasmic pattern recognition receptor signaling pathway (GO:0002753), detection of virus (GO:0009597), response to virus (GO:0009615), protein sumoylation (GO:0016925), positive regulation of interferon-alpha production (GO:0032727), positive regulation of interferon-beta production (GO:0032728), positive regulation of interleukin-6 production (GO:0032755), positive regulation of tumor necrosis factor production (GO:0032760), regulation of type III interferon production (GO:0034344), MDA-5 signaling pathway (GO:0039530), negative regulation of viral genome replication (GO:0045071), innate immune response (GO:0045087), protein complex oligomerization (GO:0051259), defense response to virus (GO:0051607), type I interferon-mediated signaling pathway (GO:0060337), positive regulation of response to cytokine stimulus (GO:0060760), cellular response to exogenous dsRNA (GO:0071360), cellular response to virus (GO:0098586), antiviral innate immune response (GO:0140374), immune system process (GO:0002376), signal transduction (GO:0007165), mRNA transcription (GO:0009299)

GO Molecular Function (17): DNA binding (GO:0003677), RNA binding (GO:0003723), RNA helicase activity (GO:0003724), double-stranded RNA binding (GO:0003725), single-stranded RNA binding (GO:0003727), ATP binding (GO:0005524), zinc ion binding (GO:0008270), ATP hydrolysis activity (GO:0016887), protein domain specific binding (GO:0019904), pattern recognition receptor activity (GO:0038187), identical protein binding (GO:0042802), ribonucleoprotein complex binding (GO:0043021), nucleotide binding (GO:0000166), helicase activity (GO:0004386), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (4): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
DDX58/IFIH1-mediated induction of interferon-alpha/beta	5
Deubiquitination	2
Innate Immune System	1
SARS-CoV-1-host interactions	1
SARS-CoV-2-host interactions	1
RSV-host interactions	1
Interferon Signaling	1
Dengue Virus-Host Interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to virus	3
positive regulation of cytokine production	2
positive regulation of type I interferon production	2
nucleic acid binding	2
RNA binding	2
ATP-dependent activity	2
protein binding	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
cytoplasm	2
pattern recognition receptor signaling pathway	1
intracellular receptor signaling pathway	1
response to other organism	1
peptidyl-lysine modification	1
protein modification by small protein conjugation	1
interferon-alpha production	1
regulation of interferon-alpha production	1
interferon-beta production	1
regulation of interferon-beta production	1
interleukin-6 production	1
regulation of interleukin-6 production	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
positive regulation of tumor necrosis factor superfamily cytokine production	1
regulation of cytokine production	1
type III interferon production	1
cytoplasmic pattern recognition receptor signaling pathway	1
viral genome replication	1
regulation of viral genome replication	1
negative regulation of viral process	1
immune response	1
defense response to symbiont	1
protein-containing complex assembly	1
defense response	1
cellular response to type I interferon	1
interferon-mediated signaling pathway	1
response to cytokine	1
positive regulation of response to stimulus	1
regulation of response to cytokine stimulus	1
response to exogenous dsRNA	1

Protein interactions and networks

STRING

3496 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IFIH1	MAVS	Q7Z434	999
IFIH1	NLRC5	Q86WI3	981
IFIH1	ATG12	O94817	978
IFIH1	DHX58	Q96C10	975
IFIH1	TLR3	O15455	970
IFIH1	ATG5	Q9H1Y0	961
IFIH1	TBK1	Q9UHD2	960
IFIH1	DDX60	Q8IY21	940
IFIH1	TRIM25	Q14258	938
IFIH1	IRF3	Q14653	938
IFIH1	IFNB1	P01574	937
IFIH1	ISG15	P05161	935
IFIH1	IKBKE	Q14164	917
IFIH1	IFIT1	P09914	914
IFIH1	IRF7	Q92985	896

IntAct

100 interactions, top by confidence:

A	B	Type	Score
MAVS	IFIH1	psi-mi:“MI:0915”(physical association)	0.770
IFIH1	MAVS	psi-mi:“MI:0915”(physical association)	0.770
MAVS		psi-mi:“MI:0914”(association)	0.730
IFIH1	IFIH1	psi-mi:“MI:0915”(physical association)	0.710
IFIH1	MAVS	psi-mi:“MI:0915”(physical association)	0.640
IFIH1	TKFC	psi-mi:“MI:0915”(physical association)	0.620
IFIH1	TKFC	psi-mi:“MI:0914”(association)	0.620
	IFIH1	psi-mi:“MI:0403”(colocalization)	0.620
	IFIH1	psi-mi:“MI:0915”(physical association)	0.620
IFIH1	ISG15	psi-mi:“MI:0915”(physical association)	0.620
IFIH1	ISG15	psi-mi:“MI:0914”(association)	0.620
P/V	IFIH1	psi-mi:“MI:0407”(direct interaction)	0.610
IFIH1	P/V	psi-mi:“MI:0915”(physical association)	0.610
P/V	IFIH1	psi-mi:“MI:0915”(physical association)	0.610
IFIH1	P/V	psi-mi:“MI:0915”(physical association)	0.590

BioGRID (110): IFIH1 (Synthetic Growth Defect), IFIH1 (Affinity Capture-MS), IFIH1 (Affinity Capture-MS), IFIH1 (Affinity Capture-MS), IFIH1 (Affinity Capture-MS), IFIH1 (Affinity Capture-MS), RNF123 (Two-hybrid), RNF123 (Affinity Capture-Western), IFIH1 (Affinity Capture-Western), MAVS (Affinity Capture-Western), IFIH1 (Affinity Capture-Western), ARRDC4 (Affinity Capture-Western), IFIH1 (Affinity Capture-Western), PPIA (Affinity Capture-Western), IFIH1 (Affinity Capture-Western)

ESM2 similar proteins: A0A023PXF5, A6QSQ0, A6SBT4, A7EY76, F1RCY6, O13559, O18475, O48534, P18708, P40105, P40434, P40889, P43538, P46063, P46459, P46460, P46461, P54351, Q14527, Q1EB85, Q2TBP1, Q2U587, Q3B7N1, Q3E7Y4, Q5R410, Q5RF63, Q6AYJ1, Q6PCN7, Q7ZU90, Q86WJ1, Q8NHQ9, Q8R5F7, Q95216, Q96C10, Q99J87, Q9BYX4, Q9CXF7, Q9DGP9, Q9EPU0, Q9FF61

Diamond homologs: A0Q7W6, A0RRM7, A1AE97, A1CBC9, A1DE13, A2RAF3, A3M7P2, A4IWK9, A4RKC3, A5ID21, A6VUP6, A7MZA8, A7NAR0, A7ZQ11, A8A377, A8FSD6, B0B7L3, B0BBS8, B0TXH8, B0VCU0, B0VTM5, B1IVR0, B1LP80, B1XB41, B2I604, B2SFY4, B2TJ22, B2TXY0, B2V4D6, B4F047, B5Z141, B6I5E1, B7GYT0, B7LDG0, B7LUZ7, B7M8I0, B7MIQ2, B7MYJ8, B7N6F5, B7NRM0

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
IFIH1	“up-regulates activity”	MAVS	binding
Viral_dsRNA	up-regulates	IFIH1
“Uridylate-specific endoribonuclease”	“down-regulates activity”	IFIH1
RIOK3	“down-regulates activity”	IFIH1	phosphorylation
PPP1CA	“up-regulates activity”	IFIH1	dephosphorylation
PPP1CC	“up-regulates activity”	IFIH1	dephosphorylation
RNF125	“down-regulates quantity by destabilization”	IFIH1	polyubiquitination
TRIM65	“up-regulates activity”	IFIH1	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 34 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Negative regulators of DDX58/IFIH1 signaling	5	70.9×	7e-07
DDX58/IFIH1-mediated induction of interferon-alpha/beta	6	66.2×	6e-08
PKR-mediated signaling	5	30.6×	4e-05
SARS-CoV-2 activates/modulates innate and adaptive immune responses	5	19.4×	2e-04
SARS-CoV Infections	6	14.5×	1e-04
Viral Infection Pathways	6	8.0×	2e-03
Infectious disease	6	6.5×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of type I interferon production	5	91.6×	4e-07
defense response to virus	6	18.1×	4e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

1758 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	25
Likely pathogenic	13
Uncertain significance	955
Likely benign	550
Benign	68

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
137621	NM_022168.4(IFIH1):c.2159G>A (p.Arg720Gln)	Pathogenic
137623	NM_022168.4(IFIH1):c.1009A>G (p.Arg337Gly)	Pathogenic
137624	NM_022168.4(IFIH1):c.2335C>T (p.Arg779Cys)	Pathogenic
140750	NM_022168.4(IFIH1):c.1354G>A (p.Ala452Thr)	Pathogenic
140751	NM_022168.4(IFIH1):c.1114C>T (p.Leu372Phe)	Pathogenic
1700152	NM_022168.4(IFIH1):c.1850T>C (p.Ile617Thr)	Pathogenic
235556	NM_022168.4(IFIH1):c.1328A>G (p.Asp443Gly)	Pathogenic
541770	NM_022168.4(IFIH1):c.2936T>G (p.Leu979Trp)	Pathogenic
623488	NM_022168.4(IFIH1):c.2439A>T (p.Glu813Asp)	Pathogenic
812522	NM_022168.4(IFIH1):c.992C>G (p.Thr331Arg)	Pathogenic
812523	NM_022168.4(IFIH1):c.992C>T (p.Thr331Ile)	Pathogenic
812525	NM_022168.4(IFIH1):c.1178A>C (p.Asp393Ala)	Pathogenic
812526	NM_022168.4(IFIH1):c.1331A>G (p.Glu444Gly)	Pathogenic
812527	NM_022168.4(IFIH1):c.1347C>G (p.Asn449Lys)	Pathogenic
812528	NM_022168.4(IFIH1):c.1465G>A (p.Ala489Thr)	Pathogenic
812529	NM_022168.4(IFIH1):c.1747A>G (p.Ile583Val)	Pathogenic
812530	NM_022168.4(IFIH1):c.2156C>T (p.Ala719Val)	Pathogenic
812531	NM_022168.4(IFIH1):c.2317G>C (p.Glu773Gln)	Pathogenic
812534	NM_022168.4(IFIH1):c.2404A>G (p.Asn802Asp)	Pathogenic
812535	NM_022168.4(IFIH1):c.2407A>T (p.Ile803Phe)	Pathogenic
812536	NM_022168.4(IFIH1):c.2471G>A (p.Arg824Lys)	Pathogenic
812537	NM_022168.4(IFIH1):c.2486C>G (p.Thr829Ser)	Pathogenic
812538	NM_022168.4(IFIH1):c.2544T>G (p.Asp848Glu)	Pathogenic
812539	NM_022168.4(IFIH1):c.2561T>A (p.Met854Lys)	Pathogenic
812540	NM_022168.4(IFIH1):c.2866A>G (p.Ile956Val)	Pathogenic
137625	NM_022168.4(IFIH1):c.1483G>A (p.Gly495Arg)	Likely pathogenic
137626	NM_022168.4(IFIH1):c.1178A>T (p.Asp393Val)	Likely pathogenic
1687394	NM_022168.4(IFIH1):c.317C>A (p.Ser106Ter)	Likely pathogenic
1706530	NM_022168.4(IFIH1):c.1246A>C (p.Ile416Leu)	Likely pathogenic
2581722	NM_022168.4(IFIH1):c.454-1G>A	Likely pathogenic

SpliceAI

2007 predictions. Top by Δscore:

Variant	Effect	Δscore
2:162267474:CTCA:C	donor_loss	1.0000
2:162267475:TCA:T	donor_loss	1.0000
2:162267476:CACC:C	donor_loss	1.0000
2:162267477:A:T	donor_loss	1.0000
2:162267478:C:CG	donor_loss	1.0000
2:162267568:CC:C	acceptor_gain	1.0000
2:162267569:CC:C	acceptor_gain	1.0000
2:162267570:C:CC	acceptor_gain	1.0000
2:162268085:A:AC	donor_gain	1.0000
2:162268086:C:CC	donor_gain	1.0000
2:162272383:CGGGC:C	acceptor_gain	1.0000
2:162272384:GGGC:G	acceptor_gain	1.0000
2:162272385:GGC:G	acceptor_gain	1.0000
2:162272385:GGCC:G	acceptor_loss	1.0000
2:162272386:GC:G	acceptor_gain	1.0000
2:162272386:GCC:G	acceptor_loss	1.0000
2:162272387:CC:C	acceptor_gain	1.0000
2:162272387:CCTGA:C	acceptor_loss	1.0000
2:162272388:C:CC	acceptor_gain	1.0000
2:162272388:CT:C	acceptor_loss	1.0000
2:162272389:T:C	acceptor_loss	1.0000
2:162273790:TGTAC:T	donor_loss	1.0000
2:162273791:GTAC:G	donor_loss	1.0000
2:162273792:TAC:T	donor_loss	1.0000
2:162273794:C:CT	donor_loss	1.0000
2:162273796:TGG:T	donor_gain	1.0000
2:162273940:TCATT:T	acceptor_gain	1.0000
2:162273941:CATT:C	acceptor_gain	1.0000
2:162273941:CATTC:C	acceptor_gain	1.0000
2:162273942:ATTCT:A	acceptor_loss	1.0000

AlphaMissense

6837 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:162267271:A:G	W1003R	0.996
2:162267271:A:T	W1003R	0.996
2:162267376:A:G	W968R	0.996
2:162267376:A:T	W968R	0.996
2:162273916:A:G	F778S	0.996
2:162273915:A:C	F778L	0.993
2:162273915:A:T	F778L	0.993
2:162273917:A:G	F778L	0.993
2:162282436:A:C	S412R	0.992
2:162282436:A:T	S412R	0.992
2:162282438:T:G	S412R	0.992
2:162288226:T:A	K335I	0.992
2:162267373:C:G	G969R	0.991
2:162267373:C:T	G969R	0.991
2:162273862:A:G	L796P	0.991
2:162281392:A:G	L487P	0.991
2:162281519:A:G	C445R	0.991
2:162268108:A:T	V929D	0.990
2:162280099:A:G	L513P	0.990
2:162281536:A:G	L439P	0.990
2:162288227:T:G	K335Q	0.990
2:162267269:C:A	W1003C	0.989
2:162267269:C:G	W1003C	0.989
2:162273937:T:G	Q771P	0.989
2:162280106:C:G	A511P	0.989
2:162267493:A:G	C962R	0.988
2:162268175:A:G	C907R	0.988
2:162280105:G:T	A511D	0.988
2:162267372:C:T	G969E	0.987
2:162277582:A:G	L626P	0.987

dbSNP variants (sampled 300 via entrez): RS1000032022 (2:162317015 G>A,C), RS1000047634 (2:162273395 C>T), RS1000048371 (2:162315426 A>G), RS1000095345 (2:162267658 G>A,T), RS1000141940 (2:162285902 C>T), RS1000161727 (2:162286489 T>C), RS1000224321 (2:162290603 T>C), RS1000233534 (2:162309912 A>C,G), RS1000297899 (2:162290937 CAGA>C), RS1000301196 (2:162290591 C>A), RS1000455633 (2:162297705 G>C), RS1000561117 (2:162292517 C>A), RS1000756038 (2:162298823 T>C), RS1000760454 (2:162284837 A>G,T), RS1000831280 (2:162297495 G>A)

Disease associations

OMIM: gene MIM:606951 | disease phenotypes: MIM:615846, MIM:182250, MIM:619773, MIM:145290, MIM:225750, MIM:114100

GenCC curated gene-disease

Disease	Classification	Inheritance
Aicardi-Goutieres syndrome 7	Definitive	Autosomal dominant
Singleton-Merten syndrome 1	Strong	Autosomal dominant
Aicardi-Goutieres syndrome	Supportive	Autosomal dominant
Singleton-Merten dysplasia	Supportive	Autosomal dominant
immunodeficiency 95	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
IFIH1-related type 1 interferonopathy	Definitive	AD

Mondo (12): Aicardi-Goutieres syndrome 7 (MONDO:0014367), Singleton-Merten syndrome 1 (MONDO:0024535), immunodeficiency 95 (MONDO:0030692), IFIH1-related type 1 interferonopathy (MONDO:0700262), basal ganglia disorder (MONDO:0003996), hyperreflexia (MONDO:0007774), vascular disorder (MONDO:0005385), prostate cancer (MONDO:0008315), Aicardi-Goutieres syndrome (MONDO:0018866), basal ganglia calcification, idiopathic, childhood-onset (MONDO:0007247), intellectual disability (MONDO:0001071), Singleton-Merten dysplasia (MONDO:0008429)

Orphanet (5): Aicardi-Goutières syndrome (Orphanet:51), Singleton-Merten dysplasia (Orphanet:85191), Familial prostate cancer (Orphanet:1331), Genetic susceptibility to infections due to particular pathogens (Orphanet:183710), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

179 total (30 of 179 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000054	Micropenis
HP:0000100	Nephrotic syndrome
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000319	Smooth philtrum
HP:0000327	Hypoplasia of the maxilla
HP:0000337	Broad forehead
HP:0000369	Low-set ears
HP:0000444	Convex nasal ridge
HP:0000496	Abnormality of eye movement
HP:0000501	Glaucoma
HP:0000508	Ptosis
HP:0000545	Myopia
HP:0000625	Eyelid coloboma
HP:0000639	Nystagmus
HP:0000670	Carious teeth
HP:0000706	Eruption failure
HP:0000737	Irritability
HP:0000819	Diabetes mellitus
HP:0000821	Hypothyroidism
HP:0000822	Hypertension
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0000958	Dry skin
HP:0000965	Cutis marmorata
HP:0000969	Edema
HP:0000988	Skin rash
HP:0000992	Cutaneous photosensitivity

GWAS associations

38 associations (top):

Study	Trait	p-value
GCST000038_12	Type 1 diabetes	2.000000e-11
GCST000392_20	Type 1 diabetes	7.000000e-09
GCST000763_5	Immunoglobulin A	7.000000e-10
GCST000833_1	Psoriasis	1.000000e-13
GCST001191_2	Type 1 diabetes	2.000000e-14
GCST001509_9	Vitiligo	5.000000e-15
GCST001725_47	Inflammatory bowel disease	2.000000e-08
GCST002738_10	Psoriasis	3.000000e-09
GCST002740_53	Inflammatory skin disease	2.000000e-12
GCST002874_14	Psoriasis	1.000000e-08
GCST002874_2	Psoriasis	5.000000e-09
GCST002874_43	Psoriasis	3.000000e-11
GCST002874_48	Psoriasis	1.000000e-07
GCST002874_7	Psoriasis	1.000000e-18
GCST003155_42	Systemic lupus erythematosus	1.000000e-11
GCST003156_35	Systemic lupus erythematosus	4.000000e-08
GCST003268_17	Psoriasis vulgaris	5.000000e-13
GCST003622_70	Systemic lupus erythematosus	3.000000e-06
GCST003814_29	Selective IgA deficiency	4.000000e-15
GCST004785_52	Vitiligo	6.000000e-25
GCST004867_6	Systemic lupus erythematosus	3.000000e-07
GCST005527_37	Psoriasis	3.000000e-08
GCST005527_5	Psoriasis	3.000000e-18
GCST005536_32	Type 1 diabetes	4.000000e-18
GCST005536_34	Type 1 diabetes	2.000000e-06
GCST005536_7	Type 1 diabetes	9.000000e-09
GCST005537_165	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	5.000000e-10
GCST005537_166	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	2.000000e-09
GCST005537_167	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	1.000000e-08
GCST005752_118	Systemic lupus erythematosus	5.000000e-12

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004747	protein measurement
EFO:1001494	psoriasis vulgaris
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0007989	monocyte percentage of leukocytes
EFO:0004833	neutrophil count

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D001480	Basal Ganglia Diseases	C10.228.140.079
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
D012021	Reflex, Abnormal	C10.597.704; C23.888.592.717; E01.370.376.550.650.655; E01.370.600.550.650.655; G11.561.731.587
D014652	Vascular Diseases	C14.907
C535607	Aicardi-Goutieres syndrome (supp.)
C536276	Idiopathic basal ganglia calcification, childhood onset (supp.)
C537343	Singleton Merten syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4739862 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — RIG-I-like receptor family

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation	3
Estradiol	affects cotreatment, increases expression, decreases expression	3
Plant Extracts	affects expression, affects reaction, affects cotreatment, increases expression	3
sodium arsenite	decreases expression, increases expression	2
epigallocatechin gallate	decreases expression, affects cotreatment	2
Acetaminophen	decreases expression, increases expression	2
Azathioprine	decreases expression	2
Lipopolysaccharides	affects expression, increases expression, affects reaction, affects response to substance	2
Nickel	increases expression	2
Poly I-C	decreases reaction, increases expression	2
Silicon Dioxide	increases expression	2
Valproic Acid	increases expression	2
Cyclosporine	decreases expression, increases expression	2
immune checkpoint inhibitor BMS-1	increases expression, increases reaction	1
alpha phellandrene	increases expression	1
alpha-pinene	increases abundance, affects cotreatment, decreases expression	1
bisphenol A	increases expression	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
trichostatin A	increases expression	1
arsenite	affects binding, decreases reaction	1
sulforaphane	increases expression	1
nickel chloride	increases expression	1
perfluorooctanoic acid	decreases expression	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
nickel sulfate	increases expression	1
hydroquinone	decreases expression	1
methacrylaldehyde	increases abundance, affects cotreatment, decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
cordycepin	increases expression, increases reaction	1
perfluorooctane sulfonic acid	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4726080	Binding	Agonist activity at human MDA5 expressed in HEK293 cells assessed as induction of IFN-inducible ISG54 promoter activity up to 10 uM after overnight incubation by secreted lucia luciferase reporter gene assay	Discovery of GS-9688 (Selgantolimod) as a Potent and Selective Oral Toll-Like Receptor 8 Agonist for the Treatment of Chronic Hepatitis B. — J Med Chem

Cellosaurus cell lines

14 cell lines: 8 cancer cell line, 3 transformed cell line, 3 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A7ZP	A549-Dual KO-MDA5	Cancer cell line	Male
CVCL_A7ZR	A549-Dual KO-MDA5 hACE2-TMPRSS2	Cancer cell line	Male
CVCL_A8BB	THP1-Dual KO-MDA5	Cancer cell line	Male
CVCL_B1FU	Abcam A-549 IFIH1 KO 1	Cancer cell line	Male
CVCL_B2ND	Abcam A-549 IFIH1 KO 2	Cancer cell line	Male
CVCL_D7A8	Leeporter HEK293T MDA5/NF-kB luciferase	Transformed cell line	Female
CVCL_D7GL	Ubigene HEK293T IFIH1 KO	Transformed cell line	Female
CVCL_D9GM	Ubigene HEK293 IFIH1 KO	Transformed cell line	Female
CVCL_F1M2	HyCyte A-549 KO-hIFIH1	Cancer cell line	Male
CVCL_SS15	HAP1 IFIH1 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01662414	PHASE4	COMPLETED	Effect of Undenatured Cysteine-Rich Whey Protein Isolate (HMS 90®) in Patients With Parkinson’s Disease
NCT04871464	PHASE4	UNKNOWN	Role and Mechanism of Probiotics in Improving Motor Symptoms in Mild to Moderate Parkinson’s Disease
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery