RIGI

Summary

RIGI (RNA sensor RIG-I, HGNC:19102) is a protein-coding gene on chromosome 9p21.1, encoding Antiviral innate immune response receptor RIG-I (O95786). Innate immune receptor that senses cytoplasmic viral nucleic acids and activates a downstream signaling cascade leading to the production of type I interferons and pro-inflammatory cytokines.

DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases which are implicated in a number of cellular processes involving RNA binding and alteration of RNA secondary structure. This gene encodes a protein containing RNA helicase-DEAD box protein motifs and a caspase recruitment domain (CARD). It is involved in viral double-stranded (ds) RNA recognition and the regulation of the antiviral innate immune response. Mutations in this gene are associated with Singleton-Merten syndrome 2.

Source: NCBI Gene 23586 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Singleton-Merten syndrome 2 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 14
• Clinical variants (ClinVar): 744 total — 2 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 16
• MANE Select transcript: NM_014314

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19102
Approved symbol	RIGI
Name	RNA sensor RIG-I
Location	9p21.1
Locus type	gene with protein product
Status	Approved
Aliases	RIG-I, FLJ13599, DKFZp434J1111, RIG-1, RIG1
Ensembl gene	ENSG00000107201
Ensembl biotype	protein_coding
OMIM	609631
Entrez	23586

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 12 protein_coding, 4 retained_intron, 3 nonsense_mediated_decay

ENST00000379868, ENST00000379883, ENST00000679662, ENST00000679665, ENST00000679771, ENST00000679859, ENST00000680733, ENST00000680883, ENST00000681352, ENST00000681448, ENST00000715269, ENST00000715270, ENST00000715271, ENST00000896058, ENST00000896059, ENST00000896060, ENST00000896061, ENST00000932231, ENST00000969568

RefSeq mRNA: 7 — MANE Select: NM_014314 NM_001385907, NM_001385909, NM_001385910, NM_001385912, NM_001385913, NM_001385914, NM_014314

CCDS: CCDS6526

Canonical transcript exons

ENST00000379883 — 18 exons

Exon	Start	End
ENSE00000695248	32481340	32481497
ENSE00000695252	32485175	32485279
ENSE00000695256	32487471	32487633
ENSE00000695259	32487945	32488203
ENSE00000695262	32488734	32488887
ENSE00000695265	32489344	32489451
ENSE00000695271	32492391	32492538
ENSE00000928040	32480219	32480354
ENSE00000928042	32526061	32526196
ENSE00000982630	32476983	32477131
ENSE00000982631	32472975	32473065
ENSE00000982632	32467762	32467932
ENSE00000982633	32466290	32466441
ENSE00001091722	32459371	32459514
ENSE00003498746	32500805	32500939
ENSE00003541740	32491301	32491420
ENSE00003683496	32493761	32493942
ENSE00003846702	32455302	32457418

Expression profiles

Bgee: expression breadth ubiquitous, 269 present calls, max score 97.08.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 43.5230 / max 3317.6072, expressed in 1666 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
100385	41.1603	1638
100386	1.6155	307
100384	0.5933	221
100379	0.1539	69

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	97.08	gold quality
upper leg skin	UBERON:0004262	88.77	gold quality
tendon of biceps brachii	UBERON:0008188	87.14	gold quality
leukocyte	CL:0000738	86.65	gold quality
monocyte	CL:0000576	86.59	gold quality
mononuclear cell	CL:0000842	86.33	gold quality
blood	UBERON:0000178	85.60	gold quality
calcaneal tendon	UBERON:0003701	85.54	gold quality
granulocyte	CL:0000094	85.39	gold quality
medial globus pallidus	UBERON:0002477	84.79	gold quality
tendon	UBERON:0000043	84.67	gold quality
superficial temporal artery	UBERON:0001614	83.88	gold quality
pericardium	UBERON:0002407	83.80	gold quality
skin of hip	UBERON:0001554	83.65	gold quality
globus pallidus	UBERON:0001875	83.07	gold quality
mucosa of paranasal sinus	UBERON:0005030	82.63	silver quality
lymph node	UBERON:0000029	82.27	gold quality
saphenous vein	UBERON:0007318	81.57	gold quality
mammary duct	UBERON:0001765	81.48	gold quality
gall bladder	UBERON:0002110	81.39	gold quality
endometrium	UBERON:0001295	81.28	gold quality
penis	UBERON:0000989	80.94	gold quality
cartilage tissue	UBERON:0002418	80.94	gold quality
trigeminal ganglion	UBERON:0001675	80.86	gold quality
smooth muscle tissue	UBERON:0001135	80.67	gold quality
descending thoracic aorta	UBERON:0002345	80.57	gold quality
nasal cavity epithelium	UBERON:0005384	80.56	silver quality
tonsil	UBERON:0002372	80.49	gold quality
endothelial cell	CL:0000115	80.39	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.27	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7037	yes	5734.76
E-MTAB-7052	yes	4105.63
E-ANND-3	yes	12.84
E-GEOD-99795	no	423.31

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ERCC6, IFI16, IRF1, IRF2, TP53, TRIM25

miRNA regulators (miRDB)

75 targeting RIGI, 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-340-5P	100.00	72.50	4437
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-182-5P	99.87	74.03	2589
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-5003-3P	99.85	69.29	2517

Literature-anchored findings (GeneRIF, showing 40)

• IFN-gamma induces the expression of RIG-I, which may play a role in the immunological effects of IFN-gamma (PMID:15181474)
• RIG-I is key in the detection and subsequent eradication of the replicating viral genomes (PMID:15208624)
• RIG-I may play some pathophysiological role in immune and inflammatory reactions in vascular smooth muscle cells(SMC). (PMID:15219805)
• Although the physiological function of RIG-I is still unknown, induction of RIG-I by IFN-gamma may play an important role in inflammatory or immunological reactions in endothelial cells. (PMID:15370293)
• hepatocytes contain two distinct antiviral signaling pathways leading to expression of intereron beta, one dependent upon TLR3 and the other dependent on RIG-I, with little cross-talk between these pathways (PMID:15737993)
• Importantly, we show that NS3/4A can strongly inhibit the ability of the recently described RIG-I protein to activate IFN, suggesting that RIG-I is a key factor in the TRIF-independent, NS3/4A-sensitive pathway. (PMID:15767399)
• Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. (PMID:16116171)
• Cardif functions as an adaptor, linking the cytoplasmic dsRNA receptor RIG-I to the initiation of antiviral programs (PMID:16177806)
• JEV and DEN-2 initiate the host innate immune response through a molecular mechanism involving RIG-I/IRF-3 and PI3K/NF-kappaB signaling pathways (PMID:16182584)
• the virus-inducible, NF-kappaB-dependent activation of A20 functions as a negative regulator of RIG-I-mediated induction of the antiviral state (PMID:16306043)
• HCV infection transiently induces RIG-I- and IPS-1-dependent IRF-3 activation (PMID:16585524)
• HCV blocks the RIG-I-mediated dsRNA signaling by an NS3/4A-independent mechanism, in addition to the NS3/4A-dependent cleavage of MAVS/IPS-1. (PMID:16707574)
• 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)
• EBERs activated RIG-I’s substrates, NF-kappaB and IFN regulatory factor 3, which were necessary for type I IFN activation. (PMID:16946700)
• results identify RIG-I as a ssRNA sensor and potential target of viral immune evasion and suggest that its ability to sense 5’-phosphorylated RNA evolved in the innate immune system as a means of discriminating between self and nonself (PMID:17038589)
• findings demonstrated that the 5’-triphosphate end of RNA generated by viral polymerases is responsible for retinoic acid-inducible protein I (RIG-I)-mediated detection of RNA molecules (PMID:17038590)
• RIG-I is required for induction of IFN-I in an influenza A virus (IAV)-infected human lung epithelial cell line. (PMID:17053203)
• We now report that the NS1 of influenza A virus interacts with RIG-I and inhibits the RIG-I-mediated induction of IFN-beta. (PMID:17079289)
• GBV-B NS3/4A protease specifically cleaves VISA and dislodges it from mitochondria, thereby disrupting its function as a RIG-I adaptor. (PMID:17093192)
• RIG-I might operate not only as a RNA helicase but also as a mediator of the cytokine network in the inflammatory skin diseases, such as psoriasis vulgaris (PMID:17182220)
• In this review, RIG-I has evolved an immune surveillance system for antiviral responses by its detection and direct binding to the 5’-end of certain viral RNA genomes, specifically, to a 5’-triphosphate group. (PMID:17307033)
• retinoic acid-inducible gene-I is expressed in lupus nephritis [letter] (PMID:17403696)
• These results confirm that by controlling RIG-I expression, IRF-1 plays an essential role in anti-viral immunity. (PMID:17516545)
• The putative dsRNA receptor RIGI may not play a pivotal role in the dsRNA-stimulated expression of inflammatory chemokines in airway epithelial cells. (PMID:17541283)
• RNA helicase cytoplasmic sensor RIG-I mediates innate antiviral signaling that is not inhibited by dihydroxyacetone kinase. (PMID:17600090)
• TNF-alpha leads to stabilization of IFN-epsilon mRNA, increased IFN-epsilon synthesis, engagement of type I IFNRs, increased STAT1 expression and phosphorylation, and up-regulation of retinoic acid-inducible gene-I expression (PMID:17878351)
• RIG-I is an essential component of the pathway relevant to polyinosinic-polycytidylic acid signaling of type I interferon in intestinal epithelial cells. (PMID:17911629)
• Our results show that PAMP receptors, TLR3, TLR7 and RIG-I mRNA levels are significantly down-regulated in patients with chronic hepatitis C infection when compared with healthy controls. (PMID:18021446)
• RIG-I may be involved in the inflammatory reaction in pericardial mesothelial cells. (PMID:18214119)
• Data show that the C-terminal domain (CTD) of RIG-I recognizes two distinct viral RNA patterns: double-stranded (ds) and 5’ppp single-stranded (ss), and suggest that the bipartite structure of CTD regulates RIG-I on encountering viral RNA patterns. (PMID:18242112)
• the C-terminal regulatory domain RD of RIG-I binds viral RNA in a 5’-triphosphate-dependent manner and activates the RIG-I ATPase by RNA-dependent dimerization. (PMID:18243112)
• A RIG-I/IFNalphabeta receptor (IFNAR)1-dependent pathway mediates SOCS1 and SOCS3 up-regulation in influenza A virus-infected bronchial epithelial cells. (PMID:18250407)
• Data show that RIG-I mRNA and protein are expressed in HeLa cells stimulated with IFN-gamma, and that RNA interference against RIG-I results in the suppression of IFN-gamma-induced CXCL11 expression. (PMID:18258269)
• a direct correlation between RNA binding and ATPase enzymatic function leading to signal transduction and suggest that a tight control of ATPase activity by the CARDs prevents RIG-I signaling in the absence of viral RNA. (PMID:18268020)
• innate cytokine responses in myeloid dendritic cells are impaired regardless of enhanced expressions of TLR2, TLR4, and RIG-I in HCV infection (PMID:18428149)
• These results establish RIG-I as a major intracellular recognition receptor for the genome of most negative-strand RNA viruses. (PMID:18446221)
• RIG-1 - MAVS interacts with cytoplasmic 100-kDa NF-kappa B2 complexes via a novel retinoic acid-inducible gene-I - NF- kappa B-inducing kinase signaling pathway (PMID:18550535)
• RIG-I-mediated co-induction of TNF and type I IFN by virus-infected primary human macrophages represents a novel innate defense mechanism to restrict viral infection in human cells. (PMID:18617992)
• Our results show that Human Metapneumovirus activates the RIG-I-MAVS signalling pathway in airway epithelial cells, leading to the expression of important proinflammatory and antiviral molecules involved in the innate immune response to viruses. (PMID:18632970)
• SUMO modification and RIG-I activation are an integral part of IRF3 and IRF7 activity that contributes to postactivation attenuation of IFN production (PMID:18635538)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Rigi	ENSMUSG00000040296
rattus_norvegicus	Rig1	ENSRNOG00000006384
caenorhabditis_elegans	drh-3	WBGENE00008400

Paralogs (2): DHX58 (ENSG00000108771), IFIH1 (ENSG00000115267)

Protein

Protein identifiers

Antiviral innate immune response receptor RIG-I — O95786 (reviewed: O95786)

Alternative names: ATP-dependent RNA helicase DDX58, DEAD box protein 58, RIG-I-like receptor 1, RNA sensor RIG-I, Retinoic acid-inducible gene 1 protein, Retinoic acid-inducible gene I protein

All UniProt accessions (9): O95786, A0A7P0T9I8, A0A7P0Z425, A0A7P0Z442, A0AAQ5BIF4, A0AAQ5BIG4, A0AAQ5BIG6, A2A376, B3KWW1

UniProt curated annotations — full annotation on UniProt →

Function. Innate immune receptor that senses cytoplasmic viral nucleic acids and activates a downstream signaling cascade leading to the production of type I interferons and pro-inflammatory cytokines. Forms a ribonucleoprotein complex with viral RNAs on which it homooligomerizes to form filaments. The homooligomerization allows the recruitment of RNF135 an E3 ubiquitin-protein ligase that activates and amplifies the RIG-I-mediated antiviral signaling in an RNA length-dependent manner through ubiquitination-dependent and -independent mechanisms. Upon activation, associates with mitochondria antiviral signaling protein (MAVS/IPS1) that activates the IKK-related kinases TBK1 and IKBKE which in turn phosphorylate the interferon regulatory factors IRF3 and IRF7, activating transcription of antiviral immunological genes including the IFN-alpha and IFN-beta interferons. Ligands include 5’-triphosphorylated ssRNAs and dsRNAs but also short dsRNAs (<1 kb in length). In addition to the 5’-triphosphate moiety, blunt-end base pairing at the 5’-end of the RNA is very essential. Overhangs at the non-triphosphorylated end of the dsRNA RNA have no major impact on its activity. A 3’overhang at the 5’triphosphate end decreases and any 5’overhang at the 5’ triphosphate end abolishes its activity. Detects both positive and negative strand RNA viruses including members of the families Paramyxoviridae: Human respiratory syncytial virus and measles virus (MeV), Rhabdoviridae: vesicular stomatitis virus (VSV), Orthomyxoviridae: influenza A and B virus, Flaviviridae: Japanese encephalitis virus (JEV), hepatitis C virus (HCV), dengue virus (DENV) and west Nile virus (WNV). It also detects rotaviruses and reoviruses. Detects and binds to SARS-CoV-2 RNAs which is inhibited by m6A RNA modifications (Ref.74). Also involved in antiviral signaling in response to viruses containing a dsDNA genome such as Epstein-Barr virus (EBV). Detects dsRNA produced from non-self dsDNA by RNA polymerase III, such as Epstein-Barr virus-encoded RNAs (EBERs). May play important roles in granulocyte production and differentiation, bacterial phagocytosis and in the regulation of cell migration.

Subunit / interactions. Monomer; maintained as a monomer in an autoinhibited state. Upon binding of viral RNAs and conformational shift, homooligomerizes and forms filaments on these molecules. Interacts (via tandem CARD domain) with MAVS/IPS1 promoting its filamentation. Interacts with DHX58/LGP2, IKBKE, TBK1 and STING1. Interacts (via CARD domain) with TRIM25 (via SPRY domain). Interacts (double-stranded RNA-bound oligomeric form) with RNF135 (homodimer); involved in RNA length-dependent activation of the RIG-I signaling pathway. Interacts with CYLD. Interacts with NLRC5; blocks the interaction of MAVS/IPS1 to RIGI. Interacts with SRC. Interacts with DDX60. Interacts with isoform 2 of ZC3HAV1 (via zinc-fingers) in an RNA-dependent manner. Interacts (via tandem CARD domain) with SEC14L1; the interaction is direct and impairs the interaction of RIGI with MAVS/IPS1. Interacts with VCP/p97; interaction is direct and allows the recruitment of RNF125 and subsequent ubiquitination and degradation. Interacts with NOP53; may regulate RIGI through USP15-mediated ‘Lys-63’-linked deubiquitination. Interacts with SIGLEC10, CBL and PTPN11; within a negative feedback loop leading to RIGI degradation. Interacts with LRRC25. Interacts with ZCCHC3; leading to activation of RIGI. Interacts with RNF123. Interacts with UBE2D3 and UBE2N; E2 ubiquitin ligases involved in RNF135-mediated ubiquitination of RIGI and activation of the RIG-I signaling pathway. Interacts with IFIT3. Interacts with DDX3X. Interacts with RTN3. Interacts with ARL16; this interaction is GTP-dependent and induced upon viral infection; this interaction suppresses the RNA sensing activity of RIGI. Interacts with DHX16; this interaction enhances RIGI-mediated antiviral response. Interacts with IRGM; promoting RIGI degradation. Interacts with IFI6; this interaction inhibits RIGI activation. Interacts with ECSIT; this interaction bridges RIGI to the MAVS complex at the mitochondrion. Interacts with YWHAE; this interaction drives RIGI at the mitochondrion. (Microbial infection) Interacts with protein Z of Guanarito virus, Machupo virus, Junin arenavirus and Sabia virus. This interaction disrupts its interaction with MAVS/IPS1, impeding downstream IRF3 and NF-kappa-B activation and resulting in decreased IFN-beta induction. (Microbial infection) Interacts (via CARD domain) with Human respiratory syncytial virus A non-structural protein 2 (NS2) and this interaction disrupts its interaction with MAVS/IPS1, impeding downstream IRF3 activation. (Microbial infection) Interacts with Rotavirus A non-structural protein 1 (NSP1) and this interaction induces down-regulation of RIGI. (Microbial infection) Interacts with paramyxoviruses (Sendai virus, Nipah virus, Measles virus and Parainfluenza virus 5) protein V; this interaction inhibits TRIM25-mediated ubiquitination of RIG-I and prevents downstream RIG-I signaling thereby inhibiting the IFN responses. (Microbial infection) Interacts with herpes simplex virus 1 protein US11; this interaction prevents the interaction of MAVS/IPS1 to RIGI. (Microbial infection) Interacts with herpes simplex virus 1 protein UL37; this interaction deaminates RIGI and inhibits its activation. (Microbial infection) Interacts with Severe fever with thrombocytopenia virus (SFTSV) NSs; this interaction this interaction sequesters RIGI in NSs-induced cytoplasmic inclusion bodies thereby inhibiting the IFN responses.

Subcellular location. Cytoplasm. Cell projection. Ruffle membrane. Cytoskeleton. Cell junction. Tight junction.

Tissue specificity. Present in vascular smooth cells (at protein level).

Post-translational modifications. Phosphorylated in resting cells and dephosphorylated in RNA virus-infected cells. Phosphorylation at Thr-770, Ser-854 and Ser-855 results in inhibition of its activity while dephosphorylation at these sites results in its activation. Ubiquitinated. ‘Lys-63’ ubiquitination by RNF135, which occurs after RNA-binding and homodimerization, releases the autoinhibition of the CARD domains by the RLR CTR domain, an essential step in the activation of the RIG-I signaling pathway. Lys-172 is the critical site of ubiquitination for MAVS/IPS1 binding and to induce anti-viral signal transduction. Lys-154, Lys-164 and Lys-172 are shared sites for RNF135-mediated and TRIM4-mediated ubiquitination. Also undergoes ‘Lys-48’ ubiquitination at Lys-181 by RNF125 that leads to proteasomal degradation. ‘Lys-48’ ubiquitination follows viral infection and is enhanced by ‘Lys-63’-linked ubiquitination of the CARD domains that promotes interaction with VCP/p97 and subsequent recruitment of RNF125. Within a negative feedback loop involving SIGLEC10 and PTPN11, ‘Lys-48’ ubiquitination at Lys-812 by CBL also elicits the proteasomal degradation of RIGI. Deubiquitinated by CYLD, a protease that selectively cleaves ‘Lys-63’-linked ubiquitin chains. Also probably deubiquitinated by USP17L2/USP17 that cleaves ‘Lys-48’- and ‘Lys-63’-linked ubiquitin chains and positively regulates the receptor. Ubiquitinated by TRIM40 via ‘Lys-48’-linked ubiquitination; leading to proteasomal degradation. Deubiquitinated by USP27X that cleaves ‘Lys-63’-linked ubiquitin chains and inhibits the innate immune receptor activity. Deubiquitinated by USP3 that also cleaves ‘Lys-63’-linked ubiquitin chains and inhibits the innate immune receptor activity. Undergoes ‘Lys-48’-linked ubiquitination catalyzed by MARCHF5 at Lys-193 and Lys-203, leading to proteasomal degradation. Phosphorylated at Ser-8 and Thr-170; these phosphorylations suppresse the TRIM25-mediated ‘Lys-63’-linked ubiquitination of RIG-I and thereby prevents RIG-I downstream signaling. Dephosphorylated by phosphatases PPP1CA/PPP1CC; this step is essential to activate RIGI and initiate downstream signaling. ISGylated. Conjugated to ubiquitin-like protein ISG15 upon IFN-beta stimulation. ISGylation negatively regulates its function in antiviral signaling response. Sumoylated, probably by MUL1; inhibiting its polyubiquitination. Acetylated in response to RNA virus infection. Deacetylated by HDAC6 in the presence of viral mRNAs which is required for detection of viral RNA by RIGI. (Microbial infection) Deamidated on Asn-495 and Asn-549 by herpes simplex virus 1 protein UL37. These modifications eliminate RIGI detection of viral RNA and restriction of viral replication. Degraded via selective autophagy following interaction with IRGM. IRGM promotes RIGI recruitment to autophagosome membranes, promoting its SQSTM1/p62-dependent autophagic degradation. (Microbial infection) Cleaved by the protease 3C of coxsackievirus B3, poliovirus and enterovirus 71 allowing the virus to disrupt the host type I interferon production. (Microbial infection) Phosphorylated at Ser-8 by herpes simplex virus 1 protein US3 leading to inhibition of critical RIGI activation steps.

Disease relevance. Singleton-Merten syndrome 2 (SGMRT2) [MIM:616298] A form of Singleton-Merten syndrome, an autosomal dominant disorder characterized by marked aortic calcification, dental anomalies, osteopenia, acro-osteolysis, and to a lesser extent glaucoma, psoriasis, muscle weakness, and joint laxity. Additional clinical manifestations include particular facial characteristics and abnormal joint and muscle ligaments. SGMRT2 is an atypical form characterized by variable expression of glaucoma, aortic calcification, and skeletal abnormalities, without dental anomalies. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The RLR CTR domain controls homooligomerization and interaction with MAVS/IPS1. In the absence of viral infection, the protein is maintained as a monomer in an autoinhibited state with the CARD domains masked through intramolecular interactions with the RLR CTR domain. Upon binding to viral RNA and ubiquitination by RNF135, a conformational change releases the autoinhibition promoting further homooligomerization, interaction of the CARD domains with the adapter protein MAVS/IPS1 and activation of the downstream RIG-I signaling pathway. The helicase domain is responsible for dsRNA recognition. The 2 CARD domains are responsible for interaction with and signaling through MAVS/IPS1 and for association with the actin cytoskeleton. The second CARD domain is the primary site for ‘Lys-63’-linked ubiquitination.

Induction. By bacterial lipopolysaccharides (LPS) in endothelial cells. By interferon (IFN).

Similarity. Belongs to the helicase family. RLR subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
O95786-1	1	yes
O95786-2	2

RefSeq proteins (7): NP_001372836, NP_001372838, NP_001372839, NP_001372841, NP_001372842, NP_001372843, NP_055129* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001650	Helicase_C-like	Domain
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR011545	DEAD/DEAH_box_helicase_dom	Domain
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
IPR042145	CARD_RIG-I_r2	Domain
IPR051363	RLR_Helicase	Family

Pfam: PF00270, PF00271, PF11648, PF16739, PF18119

Enzyme classification (BRENDA):

• EC 3.6.4.13 — RNA helicase (BRENDA: 3 organisms, 3 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (157 total): helix 46, strand 40, mutagenesis site 25, modified residue 10, cross-link 9, turn 8, domain 5, binding site 5, sequence variant 4, region of interest 2, chain 1, splice variant 1, short sequence motif 1

Structure

Experimental structures (PDB)

44 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
7BAH	X-RAY DIFFRACTION	1.89
7MK1	X-RAY DIFFRACTION	1.9
3LRR	X-RAY DIFFRACTION	2.15
3OG8	X-RAY DIFFRACTION	2.4
9KU4	ELECTRON MICROSCOPY	2.4
2YKG	X-RAY DIFFRACTION	2.5
3ZD7	X-RAY DIFFRACTION	2.5
3NCU	X-RAY DIFFRACTION	2.55
4BPB	X-RAY DIFFRACTION	2.58
3LRN	X-RAY DIFFRACTION	2.6
9KTW	ELECTRON MICROSCOPY	2.6
5F9F	X-RAY DIFFRACTION	2.6
2QFD	X-RAY DIFFRACTION	2.7
5E3H	X-RAY DIFFRACTION	2.7
4ON9	X-RAY DIFFRACTION	2.71
3ZD6	X-RAY DIFFRACTION	2.8
4AY2	X-RAY DIFFRACTION	2.8
6GPG	X-RAY DIFFRACTION	2.89
8DVU	ELECTRON MICROSCOPY	2.9
2QFB	X-RAY DIFFRACTION	3
6KYV	X-RAY DIFFRACTION	3
8DVS	ELECTRON MICROSCOPY	3
5F9H	X-RAY DIFFRACTION	3.1
7TNY	ELECTRON MICROSCOPY	3.2
7TO2	ELECTRON MICROSCOPY	3.2
8G7T	ELECTRON MICROSCOPY	3.2
5F98	X-RAY DIFFRACTION	3.28
8DVR	ELECTRON MICROSCOPY	3.3
4P4H	X-RAY DIFFRACTION	3.4
7BAI	X-RAY DIFFRACTION	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95786-F1	85.40	0.52

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 (5): 810; 813; 864; 869; 264–271

Post-translational modifications (19): 8, 8, 170, 495, 549, 770, 854, 855, 858, 909, 48, 96, 154, 164, 172, 181, 193, 203, 812

Mutagenesis-validated functional residues (25):

Position	Phenotype
8	complete loss of marchf5-mediated degradation.
55	no irf3 signaling activity. no effect on dsrna binding.
99	little or no effect on ubiquitination of the 2 card domain. abolishes ubiquitination by rnf125.
154	reduction of ubiquitination. reduction of infb induction.
164	reduction of ubiquitination. reduction of infb induction.
169	little or no effect on ubiquitination of the 2 card domains.
172	complete loss of ubiquitination. no interaction with mavs/ips1. no induction of ifn-beta.
181	little or no effect on ubiquitination of the 2 card domains.
190	little or no effect on ubiquitination of the 2 card domains.
193	little or no effect on ubiquitination of the 2 card domains.
270	no irf3 signaling activity. loss of dsrna-induced atpase activity. no effect on ds-rna binding. changed rig-i signaling
372–375	loss of dsrna-induced atpase activity. no effect on ds-rna binding. changed rig-i signaling pathway.
409–411	loss of dsrna-induced atpase activity. no effect on ds-rna binding. changed rig-i signaling pathway.
495	complete loss of herpes simplex virus 1 ul37-mediated deamidation; when associated with q-549.
549	complete loss of herpes simplex virus 1 ul37-mediated deamidation; when associated with q-495.
633–636	loss of dsrna-induced atpase activity. changed rig-i signaling pathway.
697–701	no effect on dsrna-induced atpase activity. changed rig-i signaling pathway.
726–730	loss of dsrna-induced atpase activity. changed rig-i signaling pathway.
788	decreased polyubiquitination. loss of function in rig-i signaling pathway. decreased ubiquitination and function in rig-
849	decreased ubiquitination and function in rig-i signaling pathway without effect on rna-binding; when associated with r-7
851	decreased ubiquitination and function in rig-i signaling pathway without effect on rna-binding; when associated with r-7
888	decreased ubiquitination and function in rig-i signaling pathway without effect on rna-binding; when associated with r-7
907	decreased ubiquitination and function in rig-i signaling pathway without effect on rna-binding; when associated with r-7
909	acetylation-mimic mutant which abolishes the ability to inhibit viral replication.
909	acetylation-resistant mutant which inhibits viral replication similar to the wild-type. decreased ubiquitination and fun

Function

Pathways and Gene Ontology

Reactome pathways

15 pathways

ID	Pathway
R-HSA-1169408	ISG15 antiviral mechanism
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-8983711	OAS antiviral response
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-9833110	RSV-host interactions
R-HSA-9909505	Modulation of host responses by IFN-stimulated genes

MSigDB gene sets: 474 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, REACTOME_DDX58_IFIH1_MEDIATED_INDUCTION_OF_INTERFERON_ALPHA_BETA, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, REACTOME_INNATE_IMMUNE_SYSTEM, GNF2_CASP8, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_INTERLEUKIN_8_PRODUCTION, GOBP_REGULATION_OF_DEFENSE_RESPONSE_TO_VIRUS, GOBP_RESPONSE_TO_PEPTIDE, DORN_ADENOVIRUS_INFECTION_12HR_UP, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOCC_RUFFLE

GO Biological Process (26): positive regulation of defense response to virus by host (GO:0002230), positive regulation of myeloid dendritic cell cytokine production (GO:0002735), cytoplasmic pattern recognition receptor signaling pathway (GO:0002753), detection of virus (GO:0009597), response to virus (GO:0009615), gene expression (GO:0010467), positive regulation of gene expression (GO:0010628), regulation of cell migration (GO:0030334), positive regulation of granulocyte macrophage colony-stimulating factor production (GO:0032725), 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 interleukin-8 production (GO:0032757), positive regulation of tumor necrosis factor production (GO:0032760), regulation of type III interferon production (GO:0034344), RIG-I signaling pathway (GO:0039529), response to exogenous dsRNA (GO:0043330), innate immune response (GO:0045087), positive regulation of transcription by RNA polymerase II (GO:0045944), defense response to virus (GO:0051607), positive regulation of response to cytokine stimulus (GO:0060760), cellular response to exogenous dsRNA (GO:0071360), antiviral innate immune response (GO:0140374), immune system process (GO:0002376), positive regulation of immune system process (GO:0002684), mRNA transcription (GO:0009299)

GO Molecular Function (18): double-stranded DNA binding (GO:0003690), RNA helicase activity (GO:0003724), double-stranded RNA binding (GO:0003725), single-stranded RNA binding (GO:0003727), ATP binding (GO:0005524), GTP binding (GO:0005525), zinc ion binding (GO:0008270), ATP hydrolysis activity (GO:0016887), ubiquitin protein ligase binding (GO:0031625), pattern recognition receptor activity (GO:0038187), identical protein binding (GO:0042802), nucleotide binding (GO:0000166), nucleic acid binding (GO:0003676), RNA binding (GO:0003723), helicase activity (GO:0004386), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (11): cytoplasm (GO:0005737), cytosol (GO:0005829), bicellular tight junction (GO:0005923), actin cytoskeleton (GO:0015629), ruffle membrane (GO:0032587), ribonucleoprotein complex (GO:1990904), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), membrane (GO:0016020), cell projection (GO:0042995), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
DDX58/IFIH1-mediated induction of interferon-alpha/beta	5
Antimicrobial mechanism of IFN-stimulated genes	2
Deubiquitination	2
Innate Immune System	1
SARS-CoV-1-host interactions	1
SARS-CoV-2-host interactions	1
RSV-host interactions	1
Respiratory Syncytial Virus Infection Pathway	1
Interferon Signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of cytokine production	4
cellular anatomical structure	4
response to virus	2
positive regulation of type I interferon production	2
RNA binding	2
purine ribonucleoside triphosphate binding	2
ATP-dependent activity	2
binding	2
regulation of defense response to virus by host	1
myeloid dendritic cell cytokine production	1
positive regulation of dendritic cell cytokine production	1
regulation of myeloid dendritic cell cytokine production	1
positive regulation of myeloid leukocyte mediated immunity	1
positive regulation of myeloid leukocyte cytokine production involved in immune response	1
pattern recognition receptor signaling pathway	1
intracellular receptor signaling pathway	1
response to other organism	1
macromolecule biosynthetic process	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
cell migration	1
regulation of cell motility	1
granulocyte macrophage colony-stimulating factor production	1
regulation of granulocyte macrophage colony-stimulating factor production	1
positive regulation of protein metabolic process	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
interleukin-8 production	1
regulation of interleukin-8 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

Protein interactions and networks

STRING

3896 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RIGI	MAVS	Q7Z434	999
RIGI	TRIM25	Q14258	998
RIGI	ATG5	Q9H1Y0	990
RIGI	ATG12	O94817	990
RIGI	NLRC5	Q86WI3	985
RIGI	TBK1	Q9UHD2	984
RIGI	MYOM2	P54296	983
RIGI	OASL	Q15646	974
RIGI	TLR3	O15455	968
RIGI	IFIT1	P09914	966
RIGI	TRAF3	Q13114	965
RIGI	DDX60	Q8IY21	963
RIGI	IRF3	Q14653	959
RIGI	IFNB1	P01574	956
RIGI	ISG15	P05161	953

IntAct

150 interactions, top by confidence:

A	B	Type	Score
MAVS	RIGI	psi-mi:“MI:0914”(association)	0.960
MAVS	RIGI	psi-mi:“MI:0915”(physical association)	0.960
RIGI	MAVS	psi-mi:“MI:0915”(physical association)	0.960
RIGI	MAVS	psi-mi:“MI:0914”(association)	0.960
MAVS	RIGI	psi-mi:“MI:0403”(colocalization)	0.960
TRIM25	RIGI	psi-mi:“MI:0914”(association)	0.850
TRIM25	RIGI	psi-mi:“MI:0915”(physical association)	0.850
TRIM25	RIGI	psi-mi:“MI:0403”(colocalization)	0.850
RIGI	TRIM25	psi-mi:“MI:0915”(physical association)	0.850
RIGI	TRIM25	psi-mi:“MI:0914”(association)	0.850
RIGI	N	psi-mi:“MI:0915”(physical association)	0.790
RIGI	N	psi-mi:“MI:0403”(colocalization)	0.790

BioGRID (1992): DDX58 (Biochemical Activity), MAVS (Affinity Capture-Western), DDX58 (Biochemical Activity), UBC (Reconstituted Complex), DDX58 (Reconstituted Complex), TRIM25 (Affinity Capture-Western), DDX58 (Affinity Capture-Western), UBC (Reconstituted Complex), IFIT3 (Affinity Capture-Western), MAVS (Affinity Capture-Western), USP15 (Affinity Capture-Western), USP15 (Reconstituted Complex), TIA1 (Co-fractionation), DDX58 (Biochemical Activity), RNF135 (Affinity Capture-Western)

ESM2 similar proteins: B1ARD6, B1ARD8, C0IN03, C6FG12, F1M649, F1MHT9, F2Z461, G1SRW8, O95786, P09913, P0C7P3, Q08AF3, Q2EMV9, Q2TB18, Q3UP24, Q460N5, Q5K651, Q5RCY5, Q5RCZ8, Q5U311, Q5XHI4, Q61098, Q68D06, Q692V3, Q69Z37, Q6IEE8, Q6P2S7, Q6P3V7, Q6P5U7, Q6P6V7, Q6Q899, Q6QR59, Q7Z7L1, Q86VS3, Q8BIR2, Q8CAS9, Q8CBA2, Q8IVG5, Q8IVU3, Q8IXQ6

Diamond homologs: O95786, Q6Q899, Q8R5F7, Q96C10, Q99J87, Q9BYX4, Q9GLV6, P32639, Q754U8, Q75AA7, Q9VCU9, A1DE13, A3LS22, A4RN08, A5DQF1, A6UN73, A6ZVS0, A7TSV4, I3XHK1, O59025, O73946, P40562, P44701, P46942, Q0CW42, Q0UI93, Q1DY43, Q2GID5, Q2H0G2, Q2HG76, Q2U6C4, Q2VF19, Q4WVE3, Q54CE0, Q58083, Q58900, Q5A1A0, Q5GRL3, Q5JGV6, Q5JKF2

SIGNOR signaling

22 interactions.

A	Effect	B	Mechanism
CSNK2A1	down-regulates	DDX58	phosphorylation
DDX58	“up-regulates activity”	MAVS	binding
Viral_dsRNA	up-regulates	DDX58
G3BP1	“down-regulates activity”	DDX58	binding
VCP	“down-regulates quantity by destabilization”	DDX58	ubiquitination
G3BP1	“up-regulates quantity”	DDX58
6	“down-regulates activity”	DDX58
PPP1CC	“up-regulates activity”	DDX58	dephosphorylation
PPP1CA	“up-regulates activity”	DDX58	dephosphorylation
RNF135	“up-regulates activity”	DDX58	ubiquitination
TRIM25	“up-regulates activity”	DDX58	polyubiquitination
RNF125	“down-regulates quantity by destabilization”	DDX58	polyubiquitination
LUBAC	“down-regulates activity”	DDX58	binding
CSNK2A2	“down-regulates activity”	DDX58	phosphorylation
DAPK1	“down-regulates activity”	DDX58	phosphorylation
TRIM25	“up-regulates activity”	DDX58	ubiquitination
TRIM58	“up-regulates activity”	DDX58	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 30 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	6	103.0×	4e-09
Ovarian tumor domain proteases	5	73.3×	4e-07
SARS-CoV-1 activates/modulates innate immune responses	5	71.5×	4e-07
DDX58/IFIH1-mediated induction of interferon-alpha/beta	5	66.8×	5e-07
SARS-CoV-2 activates/modulates innate and adaptive immune responses	7	32.9×	1e-07

GO biological processes:

GO term	Partners	Fold	FDR
cytoplasmic pattern recognition receptor signaling pathway	5	211.2×	7e-09
positive regulation of interferon-alpha production	5	154.3×	2e-08
positive regulation of interferon-beta production	5	93.3×	2e-07
antiviral innate immune response	5	54.2×	2e-06
positive regulation of canonical NF-kappaB signal transduction	7	24.2×	7e-07
defense response to virus	6	19.8×	2e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	3
Uncertain significance	446
Likely benign	202
Benign	55

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
189344	NM_014314.4(RIGI):c.1118A>C (p.Glu373Ala)	Pathogenic
189345	NM_014314.4(RIGI):c.803G>T (p.Cys268Phe)	Pathogenic
2635241	NM_014314.4(RIGI):c.988G>A (p.Glu330Lys)	Likely pathogenic
429298	NM_014314.4(RIGI):c.1916T>C (p.Leu639Pro)	Likely pathogenic
802476	NM_014314.4(RIGI):c.1529A>T (p.Glu510Val)	Likely pathogenic

SpliceAI

2176 predictions. Top by Δscore:

Variant	Effect	Δscore
9:32457416:TTCC:T	acceptor_loss	1.0000
9:32457417:TCC:T	acceptor_loss	1.0000
9:32457419:CT:C	acceptor_loss	1.0000
9:32457433:A:AC	acceptor_gain	1.0000
9:32457433:A:C	acceptor_gain	1.0000
9:32459366:CTTA:C	donor_loss	1.0000
9:32459367:TTA:T	donor_loss	1.0000
9:32459368:TAC:T	donor_loss	1.0000
9:32459369:A:AC	donor_gain	1.0000
9:32459370:C:CC	donor_gain	1.0000
9:32459370:C:CT	donor_loss	1.0000
9:32459370:CCT:C	donor_gain	1.0000
9:32459510:AGAAT:A	acceptor_gain	1.0000
9:32459512:AATC:A	acceptor_loss	1.0000
9:32459512:AATCT:A	acceptor_gain	1.0000
9:32459513:ATCT:A	acceptor_gain	1.0000
9:32459515:C:CC	acceptor_gain	1.0000
9:32459518:A:AC	acceptor_gain	1.0000
9:32459518:A:C	acceptor_gain	1.0000
9:32466283:GACTT:G	donor_loss	1.0000
9:32466284:ACTTA:A	donor_loss	1.0000
9:32466285:CTTAC:C	donor_loss	1.0000
9:32466286:TTACC:T	donor_loss	1.0000
9:32466287:TA:T	donor_loss	1.0000
9:32466288:A:AT	donor_loss	1.0000
9:32466289:C:T	donor_loss	1.0000
9:32466438:CTGC:C	acceptor_gain	1.0000
9:32476981:A:AC	donor_gain	1.0000
9:32476982:C:CC	donor_gain	1.0000
9:32476982:CGT:C	donor_gain	1.0000

AlphaMissense

6191 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:32466437:T:A	R730S	0.997
9:32466437:T:G	R730S	0.997
9:32487623:A:G	L408P	0.996
9:32488037:A:G	C374R	0.996
9:32488039:T:A	E373V	0.996
9:32467769:T:A	Q726H	0.995
9:32467769:T:G	Q726H	0.995
9:32487617:G:T	A410D	0.995
9:32488035:G:C	C374W	0.995
9:32488042:T:A	D372V	0.995
9:32488042:T:G	D372A	0.995
9:32466431:T:A	R732S	0.994
9:32466431:T:G	R732S	0.994
9:32466438:C:G	R730T	0.994
9:32467815:A:G	L711P	0.994
9:32467848:G:T	A700D	0.994
9:32489358:A:T	I262K	0.994
9:32457283:A:G	W873R	0.993
9:32457283:A:T	W873R	0.993
9:32467851:A:T	V699D	0.993
9:32487626:C:T	G407E	0.993
9:32488039:T:G	E373A	0.993
9:32488878:T:A	K270I	0.993
9:32488879:T:G	K270Q	0.993
9:32467840:C:G	G703R	0.992
9:32481341:C:G	R546P	0.992
9:32466432:C:G	R732T	0.990
9:32487615:A:G	S411P	0.990
9:32487620:G:A	T409I	0.990
9:32487627:C:A	G407W	0.990

dbSNP variants (sampled 300 via entrez): RS1000130302 (9:32524293 C>G), RS1000145373 (9:32474551 C>T), RS1000198420 (9:32506482 G>A,C), RS1000206224 (9:32464969 T>C,G), RS1000228654 (9:32524500 C>T), RS1000271938 (9:32458761 C>G), RS1000284727 (9:32512085 C>G,T), RS1000323230 (9:32500073 A>G), RS1000337533 (9:32511639 A>C), RS1000393110 (9:32471571 A>G), RS1000434874 (9:32489559 A>C,G), RS1000445359 (9:32471841 C>T), RS1000486740 (9:32517925 C>T), RS1000533763 (9:32487296 G>A), RS1000651766 (9:32501880 G>T)

Disease associations

OMIM: gene MIM:609631 | disease phenotypes: MIM:616298

GenCC curated gene-disease

Disease	Classification	Inheritance
Singleton-Merten syndrome 2	Strong	Autosomal dominant
Singleton-Merten dysplasia	Supportive	Autosomal dominant

Mondo (2): Singleton-Merten syndrome 2 (MONDO:0014575), Singleton-Merten dysplasia (MONDO:0008429)

Orphanet (1): Singleton-Merten dysplasia (Orphanet:85191)

HPO phenotypes

16 total (16 of 16 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000164	Abnormality of the dentition
HP:0000501	Glaucoma
HP:0000938	Osteopenia
HP:0000962	Hyperkeratosis
HP:0001650	Aortic valve stenosis
HP:0002650	Scoliosis
HP:0003621	Juvenile onset
HP:0004322	Short stature
HP:0004380	Aortic valve calcification
HP:0009771	Osteolytic defects of the phalanges of the hand
HP:0011462	Young adult onset
HP:0011463	Childhood onset
HP:0011675	Arrhythmia
HP:0025526	Psoriasiform lesion
HP:0032153	Joint subluxation

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST002738_19	Psoriasis	6.000000e-09
GCST002740_54	Inflammatory skin disease	4.000000e-12
GCST002874_16	Psoriasis	4.000000e-07
GCST003101_5	Bone mineral density (spine) and age at menarche	2.000000e-06
GCST003268_7	Psoriasis vulgaris	6.000000e-06
GCST004601_116	Red blood cell count	1.000000e-11
GCST004604_133	Hematocrit	3.000000e-10
GCST004615_62	Hemoglobin concentration	2.000000e-09
GCST005527_28	Psoriasis	8.000000e-11
GCST006585_656	Blood protein levels	8.000000e-06
GCST009391_277	Metabolite levels	6.000000e-06
GCST009391_279	Metabolite levels	8.000000e-06
GCST010083_250	Hemoglobin levels	3.000000e-11
GCST011991_25	Psoriasis or type 2 diabetes (trans-disease meta-analysis)	1.000000e-10

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0007701	spine bone mineral density
EFO:1001494	psoriasis vulgaris
EFO:0004305	erythrocyte count
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0010495	guanosine monophosphate measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537343	Singleton Merten syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs11795343	RIGI		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression, decreases methylation	7
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	4
Lipopolysaccharides	decreases expression, decreases reaction, increases expression, affects expression, affects reaction (+1 more)	4
sodium arsenite	decreases expression, increases expression	3
Nickel	decreases expression, increases expression	3
Poly I-C	decreases reaction, increases expression	3
Estradiol	affects cotreatment, increases expression	2
Plant Extracts	affects expression, affects reaction, increases expression	2
Tretinoin	increases expression, increases reaction	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
immune checkpoint inhibitor BMS-1	affects cotreatment, increases expression	1
dicrotophos	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
alpha phellandrene	increases expression	1
bisphenol A	decreases expression	1
trichostatin A	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
sulforaphane	increases expression	1
tetrabromobisphenol A	increases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	increases expression	1
chloroquine diphosphate	decreases expression	1
benzo(e)pyrene	decreases methylation	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
cordycepin	affects cotreatment, increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
15-deoxy-delta(12,14)-prostaglandin J2	decreases reaction, increases expression	1
lipopolysaccharide, E. coli O26-B6	affects reaction, increases expression	1
lipopolysaccharide, Escherichia coli O111 B4	affects reaction, increases expression	1

Cellosaurus cell lines

23 cell lines: 19 cancer cell line, 4 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_7927	Huh-7.5	Cancer cell line	Male
CVCL_A0TI	Huh-7.5 Tet-On	Cancer cell line	Male
CVCL_A7ZN	A549-Dual KO-RIG-I	Cancer cell line	Male
CVCL_A7ZS	A549-Dual KO-RIG-I hACE2-TMPRSS2	Cancer cell line	Male
CVCL_A8BC	THP1-Dual KO-RIG-I	Cancer cell line	Male
CVCL_A8CP	HEK-Lucia RIG-I	Transformed cell line	Female
CVCL_B1F0	Abcam A-549 DDX58 KO 1	Cancer cell line	Male
CVCL_B2MJ	Abcam A-549 DDX58 KO 2	Cancer cell line	Male
CVCL_C2UW	Huh-7.5 STAT1 KO #1	Cancer cell line	Male
CVCL_C2UX	Huh-7.5 STAT1 KO #2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05204771	Not specified	COMPLETED	Prenatal US Assessment of Superior Mesenteric Vessels for Digestive Rotation