CGAS

Summary

CGAS (cyclic GMP-AMP synthase, HGNC:21367) is a protein-coding gene on chromosome 6q13, encoding Cyclic GMP-AMP synthase (Q8N884). Nucleotidyltransferase that catalyzes the formation of cyclic GMP-AMP (2’,3’-cGAMP) from ATP and GTP and plays a key role in innate immunity.

Enables several functions, including 2’,3’-cyclic GMP-AMP synthase activity; molecular condensate scaffold activity; and phosphatidylinositol-4,5-bisphosphate binding activity. Involved in several processes, including intracellular signal transduction; paracrine signaling; and regulation of defense response. Located in nuclear body; plasma membrane; and site of double-strand break. Is active in cytosol and nucleus.

Source: NCBI Gene 115004 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 95 total — 1 pathogenic
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_138441

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21367
Approved symbol	CGAS
Name	cyclic GMP-AMP synthase
Location	6q13
Locus type	gene with protein product
Status	Approved
Aliases	h-cGAS, D4
Ensembl gene	ENSG00000164430
Ensembl biotype	protein_coding
OMIM	613973
Entrez	115004

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 7 protein_coding, 1 retained_intron

ENST00000370315, ENST00000370318, ENST00000459924, ENST00000680833, ENST00000858668, ENST00000858669, ENST00000918357, ENST00000918358

RefSeq mRNA: 2 — MANE Select: NM_138441 NM_001410911, NM_138441

CCDS: CCDS4978, CCDS93943

Canonical transcript exons

ENST00000370315 — 5 exons

Exon	Start	End
ENSE00001084311	73445528	73445747
ENSE00001084312	73428709	73428811
ENSE00001245869	73440209	73440445
ENSE00001292662	73423711	73425578
ENSE00001855092	73451525	73452297

Expression profiles

Bgee: expression breadth ubiquitous, 213 present calls, max score 94.68.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.7086 / max 668.0896, expressed in 1470 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
74368	12.4496	1416
74366	0.4454	191
74367	0.3557	96
74369	0.3013	159
74365	0.1566	83

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	94.68	silver quality
sperm	CL:0000019	91.64	silver quality
buccal mucosa cell	CL:0002336	91.43	silver quality
endothelial cell	CL:0000115	84.81	silver quality
monocyte	CL:0000576	84.30	gold quality
leukocyte	CL:0000738	84.23	gold quality
bone marrow cell	CL:0002092	79.04	gold quality
granulocyte	CL:0000094	79.03	gold quality
blood	UBERON:0000178	78.02	gold quality
lymph node	UBERON:0000029	77.70	gold quality
tendon of biceps brachii	UBERON:0008188	77.23	gold quality
lateral globus pallidus	UBERON:0002476	76.90	gold quality
cardia of stomach	UBERON:0001162	76.66	silver quality
nipple	UBERON:0002030	76.34	silver quality
superior surface of tongue	UBERON:0007371	76.18	silver quality
mucosa of paranasal sinus	UBERON:0005030	76.13	silver quality
ventral tegmental area	UBERON:0002691	75.95	silver quality
subthalamic nucleus	UBERON:0001906	75.78	silver quality
substantia nigra pars compacta	UBERON:0001965	75.76	silver quality
pylorus	UBERON:0001166	75.59	silver quality
dorsal plus ventral thalamus	UBERON:0001897	75.54	silver quality
vena cava	UBERON:0004087	75.54	silver quality
saphenous vein	UBERON:0007318	75.54	silver quality
inferior vagus X ganglion	UBERON:0005363	75.53	silver quality
pericardium	UBERON:0002407	75.51	silver quality
substantia nigra pars reticulata	UBERON:0001966	75.48	gold quality
trachea	UBERON:0003126	75.47	silver quality
caecum	UBERON:0001153	75.35	gold quality
lateral nuclear group of thalamus	UBERON:0002736	75.30	gold quality
renal medulla	UBERON:0000362	75.29	silver quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.85

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 40)

• These results indicate that cGAS is a cytosolic DNA sensor that induces interferons by producing the second messenger cGAMP. (PMID:23258413)
• The structure of human cGAS, revealing the similar folds of cGAS and OAS, implicates a common evolutionary ancestor as the origin of a family of structurally related but functionally distinct cytosolic nucleic acid sensors. (PMID:23707061)
• The cGAS product is actually a noncanonical cyclic dinucleotide, cyclic [G(2’-5’)pA(3’-5’)p], which contains a single 2’-5’ phosphodiester bond. (PMID:23707065)
• crystal structure of cGAS alone and in complex with DNA, ATP and GTP along with functional studies (PMID:23722159)
• These results indicate that cGAS is an innate immune sensor of HIV and other retroviruses. (PMID:23929945)
• Data indicate that cyclic GMP-AMP synthase (cGAS) is important for the stimulator of interferon genes (STING)-dependent immune activation (PMID:24116191)
• the HIV capsid is a determinant of innate sensing of the viral cDNA by cGAS in dendritic cells (PMID:24269171)
• The crystal structures of human cGAS in its apo form, representing its autoinhibited conformation as well as in its cGAMP- and sulfate-bound forms, are reported. (PMID:24462292)
• Thus, the cGAS-Beclin-1 interaction shapes innate immune responses by regulating both cGAMP production and autophagy, resulting in well-balanced antimicrobial immune responses. (PMID:24528868)
• knocking out the DNA sensor cyclic GMP-AMP synthase completely abrogates spontaneous induction of IFN-stimulated genes in TREX1-deficient cells. (PMID:24813208)
• The mechanism of double-stranded DNA sensing through the cGAS-STING pathway. (PMID:25007740)
• cGAS localized in punctate regions on the cytosolic side of the chlamydial inclusion membrane in association with STING, indicating that chlamydial DNA is most likely recognized outside the inclusion as infection progresses. (PMID:25070851)
• The cGAS/STING/TBK1/IRF3 cascade was not a direct target of viral antihost strategies, and authors found no evidence that adenovirus stimulation of the cGAS/STING DNA response had an impact on viral replication efficiency. (PMID:25297994)
• Studies in THP-1 knockout cells revealed that the recognition of RNA:DNA hybrids is completely attributable to the cGAS-STING pathway. (PMID:25425575)
• our study not only provides a novel mechanism of modulating cGAS expression, but also adds another layer of regulation in DNA-triggered IFN-I production by induction of cGAS. (PMID:25609843)
• IFI16 and cGAS cooperate in a novel way to sense nuclear herpesviral DNA and initiate innate signaling (PMID:25831530)
• Study found that PQBP1 directly binds to reverse-transcribed HIV-1 DNA and interacts with cGAS to initiate an IRF3-dependent innate response. (PMID:26046437)
• M. tuberculosis infection induces cGAS in macrophages and human lung tissue. (PMID:26048137)
• cGAS is an innate sensor of Mycobacterium tuberculosis.Mycobacterium tuberculosis differentially activates cGAS- and inflammasome-dependent intracellular immune responses through ESX-1. (PMID:26048138)
• Gammaherpesviruses encode inhibitors that block cGAS-STING-mediated antiviral immunity. (PMID:26199418)
• Knockout of cGAS and STING Rescues Virus Infection of Plasmid DNA-Transfected Cells. (PMID:26311870)
• Kaposi’s sarcoma-associated herpesvirus ORF52 subverts cytosolic DNA sensing by directly inhibiting cGAS enzymatic activity through a mechanism involving both cGAS binding and DNA binding. (PMID:26320998)
• TRIM21-induced exposure of the viral genome promotes sensing of DNA and RNA viruses by cGAS and RIG-I (PMID:26506431)
• By directly binding to cGAS, LANA, and particularly, a cytoplasmic isoform, inhibit the cGAS-STING-dependent phosphorylation of TBK1 and IRF3 and thereby antagonize the cGAS-mediated restriction of KSHV lytic replication. (PMID:26811480)
• cGAS silencing inhibited production of proinflammatory cytokines and matrix metalloproteinases (MMPs) as well as AKT and ERK phosphorylation in TNFalpha-stimulated fibroblast-like synoviocytes (PMID:26819496)
• cGAS and STING are intracellular sensors that activate the interferon pathway in response to virus infection. [review] (PMID:26867174)
• A STING-dependent, cGAS-independent pathway important for full interferon production and antiviral control of enveloped RNA viruses. (PMID:26893169)
• These results suggest that pDCs sense cytosolic DNA and cyclic dinucleotides via the cGAS-STING pathway and that targeting this pathway could be of therapeutic interest. (PMID:27125983)
• IN this review, we highlight our current understanding of DNA sensing by cGAS and its involvement in human disease (PMID:27154323)
• Type I IFN is detrimental to the host, and dysregulation of iron homeostasis genes may explain lower bacteria survival in cGAS(-/-) and TLR4(-/-) cells. (PMID:27264171)
• Primary human endothelial cells mount robust type I interferon responses to human cytomegalovirus that are dependent upon cyclic GMP-AMP synthase (cGAS), STING, and interferon regulatory factor 3 (IRF3) signaling. (PMID:27334590)
• cGAs recognizes bacterial/viral DNA, and is a strong activator of STING that can further activate IRF3 and subsequent type I interferon production. (Review) (PMID:27696330)
• Our results identify cGAS as mediator of an IFN-I response to HIV-1 infection in CD4(+) T cells and demonstrate that this response is modulated by the viral accessory proteins Vpr and Vpu. Thus, viral innate immune evasion is incomplete in the main target cells of HIV-1 (PMID:27705790)
• Results indicate that the rs311678 polymorphism in the cyclic GMP-AMP synthase (cGAS) gene confers genetic susceptibility to cervical precancerous lesions. (PMID:27705945)
• Essential roles of the cGAS-cGAMP-STING pathway. [review] (PMID:27706894)
• cGAS-STING pathway plays a role in the surveillance of hepatitis B virus infection. (PMID:27902332)
• while IFI16 induces cytokines, only cGAS activates STING/TBK-1/IRF3 and apoptotic responses upon herpes simplex virus 1 and human cytomegalovirus infections; findings show that IFI16, not cGAS or PML, represses HSV-1 gene expression, reducing virus (PMID:27935834)
• In the present study, the authors found that herpes simplex virus 1 tegument protein UL41 was involved in counteracting the cGAS/STING-mediated DNA-sensing pathway. (PMID:28077645)
• the current study demonstrated that the DNA sensor cGAS is dynamically modified by SUMO (PMID:28095500)
• Data show that both cyclic GMP-AMP synthase (cGAS) and interferon-gamma inducible protein 16 (IFI16) are required for the activation of membrane protein STING (STING) and an innate immune response to exogenous DNA and DNA viruses. (PMID:28194029)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cgasa	ENSDARG00000021572
mus_musculus	Cgas	ENSMUSG00000032344
rattus_norvegicus	Cgas	ENSRNOG00000046191
drosophila_melanogaster	CG7194	FBGN0035868
drosophila_melanogaster	cGlr2	FBGN0050424

Paralogs (9): ITPRIP (ENSG00000148841), MAB21L4 (ENSG00000172478), MAB21L3 (ENSG00000173212), MB21D2 (ENSG00000180611), MAB21L1 (ENSG00000180660), TMEM102 (ENSG00000181284), MAB21L2 (ENSG00000181541), ITPRIPL1 (ENSG00000198885), ITPRIPL2 (ENSG00000205730)

Protein

Protein identifiers

Cyclic GMP-AMP synthase — Q8N884 (reviewed: Q8N884)

Alternative names: 2'3’-cGAMP synthase, Mab-21 domain-containing protein 1

All UniProt accessions (2): Q8N884, A0A7P0TBQ3

UniProt curated annotations — full annotation on UniProt →

Function. Nucleotidyltransferase that catalyzes the formation of cyclic GMP-AMP (2’,3’-cGAMP) from ATP and GTP and plays a key role in innate immunity. Catalysis involves both the formation of a 2’,5’ phosphodiester linkage at the GpA step and the formation of a 3’,5’ phosphodiester linkage at the ApG step, producing c[G(2’,5’)pA(3’,5’)p]. Acts as a key DNA sensor: directly binds double-stranded DNA (dsDNA), inducing the formation of liquid-like droplets in which CGAS is activated, leading to synthesis of 2’,3’-cGAMP, a second messenger that binds to and activates STING1, thereby triggering type-I interferon production. Preferentially recognizes and binds curved long dsDNAs of a minimal length of 40 bp. Acts as a key foreign DNA sensor, the presence of double-stranded DNA (dsDNA) in the cytoplasm being a danger signal that triggers the immune responses. Has antiviral activity by sensing the presence of dsDNA from DNA viruses in the cytoplasm. Also acts as an innate immune sensor of infection by retroviruses, such as HIV-2, by detecting the presence of reverse-transcribed DNA in the cytosol. In contrast, HIV-1 is poorly sensed by CGAS, due to its capsid that cloaks viral DNA from CGAS detection. Detection of retroviral reverse-transcribed DNA in the cytosol may be indirect and be mediated via interaction with PQBP1, which directly binds reverse-transcribed retroviral DNA. Also detects the presence of DNA from bacteria, such as M.tuberculosis. 2’,3’-cGAMP can be transferred from producing cells to neighboring cells through gap junctions, leading to promote STING1 activation and convey immune response to connecting cells. 2’,3’-cGAMP can also be transferred between cells by virtue of packaging within viral particles contributing to IFN-induction in newly infected cells in a cGAS-independent but STING1-dependent manner. Also senses the presence of neutrophil extracellular traps (NETs) that are translocated to the cytosol following phagocytosis, leading to synthesis of 2’,3’-cGAMP. In addition to foreign DNA, can also be activated by endogenous nuclear or mitochondrial DNA. When self-DNA leaks into the cytosol during cellular stress (such as mitochondrial stress, SARS-CoV-2 infection causing severe COVID-19 disease, DNA damage, mitotic arrest or senescence), or is present in form of cytosolic micronuclei, CGAS is activated leading to a state of sterile inflammation. Acts as a regulator of cellular senescence by binding to cytosolic chromatin fragments that are present in senescent cells, leading to trigger type-I interferon production via STING1 and promote cellular senescence. Also involved in the inflammatory response to genome instability and double-stranded DNA breaks: acts by localizing to micronuclei arising from genome instability. Micronuclei, which are frequently found in cancer cells, consist of chromatin surrounded by their own nuclear membrane: following breakdown of the micronuclear envelope, a process associated with chromothripsis, CGAS binds self-DNA exposed to the cytosol, leading to 2’,3’-cGAMP synthesis and subsequent activation of STING1 and type-I interferon production. Activated in response to prolonged mitotic arrest, promoting mitotic cell death. In a healthy cell, CGAS is however kept inactive even in cellular events that directly expose it to self-DNA, such as mitosis, when cGAS associates with chromatin directly after nuclear envelope breakdown or remains in the form of postmitotic persistent nuclear cGAS pools bound to chromatin. Nuclear CGAS is inactivated by chromatin via direct interaction with nucleosomes, which block CGAS from DNA binding and thus prevent CGAS-induced autoimmunity. Also acts as a suppressor of DNA repair in response to DNA damage: inhibits homologous recombination repair by interacting with PARP1, the CGAS-PARP1 interaction leading to impede the formation of the PARP1-TIMELESS complex. In addition to DNA, also sense translation stress: in response to translation stress, translocates to the cytosol and associates with collided ribosomes, promoting its activation and triggering type-I interferon production. In contrast to other mammals, human CGAS displays species-specific mechanisms of DNA recognition and produces less 2’,3’-cGAMP, allowing a more fine-tuned response to pathogens.

Subunit / interactions. Monomer in the absence of DNA. Homodimer in presence of dsDNA: forms a 2:2 dimer with two enzymes binding to two DNA molecules. Interacts with nucleosomes; interaction is mainly mediated via histones H2A and H2B and inactivates the nucleotidyltransferase activity by blocking DNA-binding and subsequent activation. Interacts with PQBP1 (via WW domain). Interacts with TRIM14; this interaction recruits USP14, leading to deubiquitinate and stabilize CGAS and promote type I interferon production. Interacts with ZCCHC3; promoting sensing of dsDNA by CGAS. Interacts (when not monomethylated) with (poly-ADP-ribosylated) PARP1; interaction takes place in the nucleus and prevents the formation of the PARP1-TIMELESS complex. Interacts (when monomethylated) with SGF29; interaction with SGF29 prevents interaction with PARP1. Interacts with PCBP2; preventing the formation of liquid-like droplets in which CGAS is activated. Interacts with IRGM; promoting CGAS degradation. Interacts with DDX41. (Microbial infection) Interacts with herpes virus 8/HHV-8 protein ORF52; this interaction inhibits cGAS enzymatic activity by preventing the formation of liquid-like droplets by CGAS. (Microbial infection) Interacts with herpes simplex virus 1 protein UL37; this interaction deaminates CGAS and inhibits its activation. (Microbial infection) Interacts with vaccinia virus protein OPG067; this interaction promotes CGAS proteasomal degradation. (Microbial infection) Interacts with cytomegalovirus protein UL31; this interaction promotes dissociation of DNA from CGAS, thereby inhibiting the enzymatic activity of CGAS. (Microbial infection) Interacts with herpes simplex virus 1 tegument protein VP22 (UL49); this interaction inhibits cGAS enzymatic activity by preventing the formation of liquid-like droplets by CGAS. (Microbial infection) Interacts with herpesvirus 3 tegument protein VP22 (ORF9); this interaction inhibits cGAS enzymatic activity by preventing the formation of liquid-like droplets by CGAS. (Microbial infection) Interacts with human cytomegalovirus proteins UL42 and UL83; these interactions result in the inhibition of cGAS-STING signaling.

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

Tissue specificity. Expressed in the monocytic cell line THP1.

Post-translational modifications. The N-terminal disordered part (1-160) is phosphorylated by AURKB during the G2-M transition, blocking CGAS liquid phase separation and preventing activation. Phosphorylation at Tyr-215 by BLK promotes cytosolic retention. Localizes into the nucleus following dephosphorylation at Tyr-215. Phosphorylation at Ser-435 activates the nucleotidyltransferase activity. Dephosphorylation at Ser-435 by PPP6C impairs its ability to bind GTP, thereby inactivating it. Phosphorylation at Thr-68 and Ser-213 by PRKDC inhibits its cyclic GMP-AMP synthase activity by impairing homodimerization and activation. Phosphorylation at Ser-305 by AKT (AKT1, AKT2 or AKT3) suppresses the nucleotidyltransferase activity. Phosphorylation at Ser-305 by CDK1 during mitosis leads to its inhibition, thereby preventing CGAS activation by self-DNA during mitosis. Dephosphorylated at Ser-305 by protein phosphatase PP1 upon mitotic exit. Ubiquitinated at Lys-414 via ‘Lys-48’-linked polyubiquitin chains, leading to its SQSTM1-mediated autophagic degradation. Interaction with TRIM14 promotes recruitment of USP14, leading to deubiquitinate Lys-414 and stabilize CGAS. Ubiquitinated at Lys-173 and Lys-384 by RNF185 via ‘Lys-27’-linked polyubiquitination, promoting CGAS cyclic GMP-AMP synthase activity. Monoubiquitination at Lys-347 by TRIM56 promotes oligomerization and subsequent activation. Monoubiquitination by TRIM41 promotes CGAS activation. Ubiquitination at Lys-285 and Lys-479 via ‘Lys-48’-linked polyubiquitination promotes its degradation. Deubiquitination at Lys-285 by USP29 promotes its stabilization. Deubiquitinated by USP27X, promoting its stabilization. Ubiquitinated at Lys-411 via ‘Lys-63’-linked polyubiquitin chains by MARCHF8, leading to the inhibition of its DNA binding ability. In cycling cells, nucleosome-bound CGAS is ubiquitinated at Lys-427 and Lys-428 via ‘Lys-48’-linked polyubiquitin chains by the ECS(SPSB3) complex, leading to its degradation: ubiquitination and degradation of nuclear CGAS during G1 and G2 phases is required to promote low intranuclear CGAS abundance before the next mitotic cycle. Sumoylated at Lys-231 and Lys-479 by TRIM38 in uninfected cells and during the early phase of viral infection, promoting its stability by preventing ubiquitination at Lys-285 and Lys-479, and subsequent degradation. Desumoylated by SENP2 during the late phase of viral infection. Sumoylation at Lys-347, Lys-384 and Lys-394 prevents DNA-binding, oligomerization and nucleotidyltransferase activity. Desumoylation at Lys-347, Lys-384 and Lys-394 by SENP7 relieves inhibition and activates CGAS. Polyglutamylated by TTLL6 at Glu-286, leading to impair DNA-binding activity. Monoglutamylated at Glu-314 by TTLL4, leading to impair the nucleotidyltransferase activity. Deglutamylated by AGBL5/CCP5 and AGBL6/CCP6. Acetylation at Lys-384, Lys-394 and Lys-414 inhibits the cyclic GMP-AMP synthase activity. Deacetylated upon cytosolic DNA challenge such as viral infections. Acetylation can be mediated by aspirin (acetylsalicylate) drug, which directly acetylates CGAS. Acetylation by aspirin efficiently inhibits CGAS-mediated immune responses and is able to suppress self-DNA-induced autoimmunity. Acetylation at Lys-47, Lys-56, Lys-62 and Lys-83 by KAT5 increases the cyclic GMP-AMP synthase activity by promoting DNA-binding and subsequent activation. Proteolytically cleaved by apoptotic caspases during apoptosis, leading to its inactivation. The damage of the nucleus and the mitochondria during apoptosis leads to leakage of nuclear and mitochondrial DNA, which activate CGAS: cleavage and inactivation during apoptosis in required to prevent cytokine overproduction. Cleaved by CASP3 at Asp-319 during virus-induced apoptosis, thereby inactivating it and preventing cytokine overproduction. Cleaved by CASP1 at Asp-140 and Asp-157 upon DNA virus infection; the cleavage impairs cGAMP production. Also cleaved by the pyroptotic CASP4 and CASP5 during non-canonical inflammasome activation; they don’t cut at the same sites as CASP1. Degraded via selective autophagy following interaction with IRGM. IRGM promotes CGAS recruitment to autophagosome membranes, promoting its SQSTM1/p62-dependent autophagic degradation. Poly-ADP-ribosylation at Asp-191 by PARP1 impairs DNA-binding, thereby preventing the cyclic GMP-AMP synthase activity. Palmitoylation at Cys-474 by ZDHHC18 impairs DNA-binding, thereby preventing the cyclic GMP-AMP synthase activity. Palmitoylation at Cys-404 and Cys-405 by ZDHHC9 promotes homodimerization and cyclic GMP-AMP synthase activity. Depalmitoylation at Cys-404 and Cys-405 by LYPLAL1 impairs homodimerization and cyclic GMP-AMP synthase activity. Monomethylated at Lys-506 by SETD7. Monomethylation promotes interaction with SGF29, preventing interaction between PARP1 nad SGF29. Demethylation by RIOX1 promotes interaction with PARP1, followed by PARP1 inactivation. Lactylation by AARS2 prevents ability to undergo liquid-liquid phase separation (LLPS), thereby inhibiting CGAS activation. (Microbial infection) Deamidated on ‘Asn-210’ by herpes simplex virus 1 protein UL37. This modification significantly reduces CGAS-dependent cGAMP production and innate immune signaling induced by dsDNA. (Microbial infection) Degraded by an autophagy-mediated mechanism in presence of Chikungunya virus capsid protein.

Activity regulation. The enzyme activity is strongly increased by double-stranded DNA (dsDNA), but not by single-stranded DNA or RNA. DNA-binding induces the formation of liquid-like droplets in which CGAS is activated. Liquid-like droplets also create a selective environment that restricts entry of negative regulators, such as TREX1 or BANF1/BAF, allowing sensing of DNA. A number of mechanisms exist to restrict its activity toward self-DNA. The nucleotidyltransferase activity is inhibited in the nucleus via its association with nucleosomes: interacts with the acidic patch of histones H2A and H2B, thereby blocking DNA-binding and subsequent activation. CGAS is also inactive when associated with mitotic chromatin. Chromatin-bound CGAS cannot be activated by exogenous DNA in mitotic cells: phosphorylation of the N-terminal disordered part by AURKB during the G2-M transition blocks CGAS liquid phase separation and activation. Activity toward self-DNA is inhibited by BANF1/BAF upon acute loss of nuclear membrane integrity: BANF1/BAF acts by outcompeting CGAS for DNA-binding, thereby preventing CGAS activation. DNA-induced activation at micronuclei is also limited by TREX1, which degrades micronuclear DNA upon nuclear envelope rupture, thereby preventing CGAS activation. CGAS can be released from nucleosomes and activated by MRE11 component of the MRN complex, which displaces CGAS from acidic-patch-mediated sequestration. Acetylation at Lys-384, Lys-394 and Lys-414 inhibits the cyclic GMP-AMP synthase activity. Inhibited by aspirin (acetylsalicylate) drug, which acetylates CGAS. Acetylation by KAT5 increases the cyclic GMP-AMP synthase activity by promoting DNA-binding and subsequent activation. Phosphorylation at Ser-305 suppresses the nucleotidyltransferase activity. Phosphorylation at Ser-435 promotes the cyclic GMP-AMP synthase activity. Phosphorylation at Thr-68 and Ser-213 inhibits its cyclic GMP-AMP synthase activity. Ubiquitination at Lys-173 and Lys-384 via ‘Lys-27’-linked polyubiquitination enhances the cyclic GMP-AMP synthase activity. Monoubiquitination at Lys-347 promotes oligomerization and subsequent activation. Sumoylation at Lys-347, Lys-384 and Lys-394 prevents DNA-binding, oligomerization and nucleotidyltransferase activity. The enzyme activity is impaired by the cleavage at Asp-140 and Asp-157 produced by CASP1. In addition to DNA, also activated by collided ribosomes upon translation stress: specifically binds collided ribosomes, promoting its activation and triggering type-I interferon production. Strongly inhibited by compound PF-06928215, which is specific for human protein. Inhibited by small-molecule inhibitors with a pyridoindole tricyclic core G108, G140 and G150. (Microbial infection) Nucleotidyltransferase activity is inhibited by different herpesvirus tegument proteins (Herpes simplex virus 1 tegument protein VP22, herpes virus 8 protein ORF52 and herpesvirus 3 tegument protein VP22/ORF9). Viral tegument proteins act by disrupting liquid-like droplets in which CGAS is activated, thereby preventing CGAS activity.

Cofactor. Binds 1 Mg(2+) ion per subunit. Is also active with Mn(2+). Mn(2+)-activated enzyme forms an inverted pppGp(2’-5’)A intermediate, suggesting a non-canonical but accelerated 2’,3’-cGAMP cyclization without substrate flip-over. Mn(2+) ions are coordinated by triphosphate moiety of the inverted substrate, independent of the catalytic triad residues. Undergoes a liquid-like phase transition after binding to DNA, which is dependent on zinc.

Domain organisation. Lys-187 and Leu-195 residues are specific to human and destabilize the interactions with short DNA, shifting the specificity toward the detection of curved long DNAs. Lys-187 and Leu-195 also restrain cGAMP production and, therefore, immune activation, allowing a more fine-tuned response to pathogens. The N-terminal disordered part (1-160) binds unspecifically dsDNA and expands the binding and moving range of CGAS on dsDNA. The disordered and positively charged residues enhance CGAS-DNA phase separation by increasing the valencies of DNA-binding. The N-terminus is required to sense chromatin and its phosphorylation blocks its activation by chromatin DNA. When the N-terminal part (1-160) is missing the protein bound to dsDNA homodimerizes. The arginine-anchor tightly binds to the canonical H2A acidic-patch residues.

Induction. By type I interferons.

Miscellaneous. The cGAS-STING signaling pathway drives sterile inflammation leading to type I interferon immunopathology in severe COVID-19 disease caused by SARS-CoV-2 virus infection. Tissue damages in the lung and skin lesions are caused by activation of the cGAS-STING signaling leading to aberrant inflammation. Endothelial cell damage is also caused by activation of the cGAS-STING pathway: SARS-CoV-2 infection triggers mitochondrial DNA release into the cytosol. Released mitochondrial DNA is then detected by CGAS, leading to activation of the cGAS-STING pathway, triggering type-I interferon production and autoinflammation.

Similarity. Belongs to the mab-21 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8N884-1	1	yes
Q8N884-2	2

RefSeq proteins (2): NP_001397840, NP_612450* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR024810	MAB21L/cGLR	Family
IPR046903	Mab-21-like_nuc_Trfase	Domain
IPR046906	Mab-21_HhH/H2TH-like	Domain

Pfam: PF03281, PF20266

Enzyme classification (BRENDA):

• EC 2.7.7.86 — cyclic GMP-AMP synthase (BRENDA: 4 organisms, 8 substrates, 53 inhibitors, 1 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 3 shown:

• GTP + ATP = pppGp(2’-5’)A + diphosphate (RHEA:23748)
• pppGp(2’-5’)A = 2’,3’-cGAMP + diphosphate (RHEA:23924)
• GTP + ATP = 2’,3’-cGAMP + 2 diphosphate (RHEA:42064)

UniProt features (273 total): mutagenesis site 129, modified residue 36, strand 20, binding site 19, helix 17, cross-link 14, region of interest 7, turn 7, site 6, short sequence motif 4, compositionally biased region 4, sequence variant 4, lipid moiety-binding region 3, splice variant 2, chain 1

Structure

Experimental structures (PDB)

107 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9MDC	X-RAY DIFFRACTION	1.25
7FUA	X-RAY DIFFRACTION	1.44
7FTJ	X-RAY DIFFRACTION	1.46
9C8T	X-RAY DIFFRACTION	1.47
7FTF	X-RAY DIFFRACTION	1.51
9ELX	X-RAY DIFFRACTION	1.53
9C8N	X-RAY DIFFRACTION	1.55
9MDD	X-RAY DIFFRACTION	1.6
7FUK	X-RAY DIFFRACTION	1.61
7FTR	X-RAY DIFFRACTION	1.64
7FTU	X-RAY DIFFRACTION	1.65
7FU9	X-RAY DIFFRACTION	1.67
7FTM	X-RAY DIFFRACTION	1.7
7FUR	X-RAY DIFFRACTION	1.7
7FU8	X-RAY DIFFRACTION	1.72
7FTG	X-RAY DIFFRACTION	1.73
7FUI	X-RAY DIFFRACTION	1.74
7FUQ	X-RAY DIFFRACTION	1.76
7FUJ	X-RAY DIFFRACTION	1.79
8IMG	X-RAY DIFFRACTION	1.8
7FUO	X-RAY DIFFRACTION	1.81
7FU3	X-RAY DIFFRACTION	1.82
6LRC	X-RAY DIFFRACTION	1.83
7FTV	X-RAY DIFFRACTION	1.88
7FUF	X-RAY DIFFRACTION	1.92
9LIO	X-RAY DIFFRACTION	1.92
7FU4	X-RAY DIFFRACTION	1.93
7FUH	X-RAY DIFFRACTION	1.94
4LEV	X-RAY DIFFRACTION	1.95
4MKP	X-RAY DIFFRACTION	1.95

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N884-F1	78.38	0.60

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 (6): 140–141 (cleavage; by casp1); 157–158 (cleavage; by casp1); 187 (important for preferential detection of curved long dna); 195 (important for preferential detection of curved long dna); 255 (arginine-anchor); 319–320 (cleavage; by casp3)

Ligand- & substrate-binding residues (19): 211; 213; 225–227; 225; 227; 227; 319; 319; 319; 362; 376–383; 376 …

Post-translational modifications (53): 7, 13, 21, 37, 47, 50, 56, 62, 63, 64, 68, 82, 83, 91, 98, 116, 129, 131, 143, 191 …

Mutagenesis-validated functional residues (129):

Position	Phenotype
7	acetylation-mimetic mutant; no effect.
7	no effect.
13	in 20de phospho-mimetic mutant; causes inactivation of nucleotidyltransferase activity; when associated with e-18; d-23;
18	in 20de phospho-mimetic mutant; causes inactivation of nucleotidyltransferase activity; when associated with d-13; d-23;
23	in 20de phospho-mimetic mutant; causes inactivation of nucleotidyltransferase activity; when associated with d-13; e-18;
33	no effect on type i ifn and rsad2 induction. no effect on cleavage by casp1. no effect on cleavage by casp1; when associ
35	in 20de phospho-mimetic mutant; causes inactivation of nucleotidyltransferase activity; when associated with d-13; e-18;
37	in 20de phospho-mimetic mutant; causes inactivation of nucleotidyltransferase activity; when associated with d-13; e-18;
47	decreased acetylation by kat5, leading to decreased stimulation of interferon production.
50	acetylation-mimetic mutant; no effect.
50	no effect.
56	decreased acetylation by kat5, leading to decreased stimulation of interferon production.
57	in 20de phospho-mimetic mutant; causes inactivation of nucleotidyltransferase activity; when associated with d-13; e-18;
59	in 20de phospho-mimetic mutant; causes inactivation of nucleotidyltransferase activity; when associated with d-13; e-18;
62	decreased acetylation by kat5, leading to decreased stimulation of interferon production.
64	in 20de phospho-mimetic mutant; causes inactivation of nucleotidyltransferase activity; when associated with d-13; e-18;
67	no effect on type i ifn and rsad2 induction. no effect on cleavage by casp1; when associated with a-33; a-90 and a-95. h
68	phospho-mimetic mutant; decreased nucleotidyltransferase activity. in 20de phospho-mimetic mutant; causes inactivation o
71–75	abolished binding to phosphatidylinositol 4,5-bisphosphate (ptdins(4,5)p2) and abolished association with the cell membr
77	in 20de phospho-mimetic mutant; causes inactivation of nucleotidyltransferase activity; when associated with d-13; e-18;
83	decreased acetylation by kat5, leading to decreased stimulation of interferon production.
90	no effect on type i ifn and rsad2 induction. no effect on cleavage by casp1; when associated with a-33; a-67 and a-95. h
91	in 20de phospho-mimetic mutant; causes inactivation of nucleotidyltransferase activity; when associated with d-13; e-18;
94	in 20de phospho-mimetic mutant; causes inactivation of nucleotidyltransferase activity; when associated with d-13; e-18;
95	no effect on type i ifn and rsad2 induction. no effect on cleavage by casp1; when associated with a-33; a-67 and a-90. h

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1834941	STING mediated induction of host immune responses
R-HSA-9920588	Dengue virus activates/modulates innate and adaptive immune responses

MSigDB gene sets: 210 (showing top): GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_DNA_RECOMBINATION, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, GOBP_REGULATION_OF_DEFENSE_RESPONSE_TO_VIRUS, PEREZ_TP63_TARGETS, GOBP_NEGATIVE_REGULATION_OF_DNA_REPAIR, GOBP_NEGATIVE_REGULATION_OF_DNA_RECOMBINATION, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR_VIA_HOMOLOGOUS_RECOMBINATION, GOBP_CELLULAR_SENESCENCE, GOBP_REGULATION_OF_DNA_REPAIR

GO Biological Process (26): activation of innate immune response (GO:0002218), pattern recognition receptor signaling pathway (GO:0002221), positive regulation of defense response to virus by host (GO:0002230), regulation of immunoglobulin production (GO:0002637), cytoplasmic pattern recognition receptor signaling pathway (GO:0002753), DNA repair (GO:0006281), DNA damage response (GO:0006974), determination of adult lifespan (GO:0008340), positive regulation of type I interferon production (GO:0032481), paracrine signaling (GO:0038001), innate immune response (GO:0045087), regulation of T cell activation (GO:0050863), defense response to virus (GO:0051607), cellular response to exogenous dsRNA (GO:0071360), cGAS/STING signaling pathway (GO:0140896), negative regulation of cGAS/STING signaling pathway (GO:0160049), negative regulation of double-strand break repair via homologous recombination (GO:2000042), positive regulation of cellular senescence (GO:2000774), immune system process (GO:0002376), obsolete cAMP-mediated signaling (GO:0019933), obsolete cGMP-mediated signaling (GO:0019934), signal transduction involved in regulation of gene expression (GO:0023019), regulation of type I interferon production (GO:0032479), negative regulation of DNA repair (GO:0045738), regulation of immune response (GO:0050776), positive regulation of cytokine production involved in inflammatory response (GO:1900017)

GO Molecular Function (18): DNA binding (GO:0003677), chromatin binding (GO:0003682), double-stranded DNA binding (GO:0003690), ATP binding (GO:0005524), GTP binding (GO:0005525), phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), nucleosome binding (GO:0031491), protein homodimerization activity (GO:0042803), metal ion binding (GO:0046872), 2’,3’-cyclic GMP-AMP synthase activity (GO:0061501), molecular condensate scaffold activity (GO:0140693), poly-ADP-D-ribose modification-dependent protein binding (GO:0160004), nucleotide binding (GO:0000166), protein binding (GO:0005515), lipid binding (GO:0008289), transferase activity (GO:0016740), nucleotidyltransferase activity (GO:0016779), identical protein binding (GO:0042802)

GO Cellular Component (9): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), nuclear body (GO:0016604), site of double-strand break (GO:0035861), chromosome (GO:0005694), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Cytosolic sensors of pathogen-associated DNA	1
Dengue Virus-Host Interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
binding	3
positive regulation of cytokine production	2
purine ribonucleoside triphosphate binding	2
intracellular membraneless organelle	2
activation of immune response	1
positive regulation of innate immune response	1
innate immune response-activating signaling pathway	1
regulation of defense response to virus by host	1
immunoglobulin production	1
regulation of production of molecular mediator of immune response	1
pattern recognition receptor signaling pathway	1
intracellular receptor signaling pathway	1
DNA metabolic process	1
DNA damage response	1
cellular response to stress	1
multicellular organismal process	1
regulation of type I interferon production	1
type I interferon production	1
cell-cell signaling	1
immune response	1
defense response to symbiont	1
T cell activation	1
regulation of lymphocyte activation	1
defense response	1
response to virus	1
response to exogenous dsRNA	1
cellular response to dsRNA	1
cytoplasmic pattern recognition receptor signaling pathway	1
negative regulation of cytoplasmic pattern recognition receptor signaling pathway	1
cGAS/STING signaling pathway	1
double-strand break repair via homologous recombination	1
regulation of double-strand break repair via homologous recombination	1
negative regulation of DNA recombination	1
negative regulation of double-strand break repair	1
positive regulation of cellular process	1
cellular senescence	1
regulation of cellular senescence	1
biological_process	1
nucleic acid binding	1

Protein interactions and networks

STRING

2048 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CGAS	BECN1	Q14457	988
CGAS	TBK1	Q9UHD2	921
CGAS	RIGI	O95786	897
CGAS	STING1	Q86WV6	894
CGAS	IRF3	Q14653	891
CGAS	IFI16	Q16666	886
CGAS	DDX41	Q9UJV9	871
CGAS	IFIH1	Q9BYX4	856
CGAS	NONO	P30807	834
CGAS	TLR9	Q9NR96	813
CGAS	G3BP1	Q13283	809
CGAS	MAVS	Q7Z434	803
CGAS	IFNB1	P01574	802
CGAS	AIM2	O14862	796
CGAS	TLR7	Q9NYK1	781

IntAct

25 interactions, top by confidence:

A	B	Type	Score
ZCCHC3	CGAS	psi-mi:“MI:0915”(physical association)	0.600
CGAS	ZCCHC3	psi-mi:“MI:0915”(physical association)	0.600
ZCCHC3	CGAS	psi-mi:“MI:0407”(direct interaction)	0.600
CGAS	PARP1	psi-mi:“MI:0915”(physical association)	0.580
CGAS	PARP1	psi-mi:“MI:0914”(association)	0.580
H2AX	CGAS	psi-mi:“MI:0915”(physical association)	0.520
CGAS	H2AX	psi-mi:“MI:0915”(physical association)	0.520
	CGAS	psi-mi:“MI:0407”(direct interaction)	0.440
CGAS	SERPINB5	psi-mi:“MI:0915”(physical association)	0.400
CGAS		psi-mi:“MI:0915”(physical association)	0.400
CGAS	Kpna2	psi-mi:“MI:0915”(physical association)	0.400
CGAS	Kpna3	psi-mi:“MI:0915”(physical association)	0.400
Kpna4	CGAS	psi-mi:“MI:0915”(physical association)	0.400
PHF8	MACROH2A1	psi-mi:“MI:0914”(association)	0.350
MPHOSPH8	HCFC1	psi-mi:“MI:0914”(association)	0.350
Espl1	BDP1	psi-mi:“MI:0914”(association)	0.350
Mus81	KIF1B	psi-mi:“MI:0914”(association)	0.350
LDHD	METTL8	psi-mi:“MI:0914”(association)	0.350
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
CGAS	HSPA4L	psi-mi:“MI:0914”(association)	0.350
FTL		psi-mi:“MI:0914”(association)	0.350

BioGRID (392): MB21D1 (Affinity Capture-MS), MB21D1 (Affinity Capture-MS), MB21D1 (Affinity Capture-MS), MB21D1 (Affinity Capture-MS), MB21D1 (Affinity Capture-MS), ZNF593 (Affinity Capture-MS), MB21D1 (Affinity Capture-Western), RNF185 (Affinity Capture-Western), MB21D1 (Biochemical Activity), MB21D1 (Affinity Capture-MS), TRIM41 (Affinity Capture-Western), MB21D1 (Affinity Capture-MS), USP10 (Affinity Capture-MS), RAI14 (Affinity Capture-MS), TGM2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0K3AV08, A0A0L0P4F8, A0A8B8BQ58, A0A913XCT1, A7SFB5, A8DYP7, B3NQ14, G5EGA3, H2KZW3, O95251, P04786, P04867, P07799, P0DXB4, P0DXB6, P0DXB9, P11387, P13864, P26358, P30181, P32644, P34607, P41512, P52439, P93119, Q00313, Q04750, Q07050, Q197A8, Q21209, Q23243, Q23541, Q24K09, Q27746, Q2QUS0, Q552Z6, Q5SVQ0, Q5UQH6, Q61T02, Q6R7H5

Diamond homologs: E1BGN7, I3LM39, Q8C6L5, Q8N884, Q567X9

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
CGAS	“down-regulates activity”	DNA_repair
PPP6C	“down-regulates activity”	CGAS	dephosphorylation
TRIM41	“up-regulates activity”	CGAS	ubiquitination
SYK	“up-regulates activity”	CGAS	phosphorylation
BLK	“down-regulates activity”	CGAS	phosphorylation
CDK1	“down-regulates activity”	CGAS	phosphorylation
CGAS	“up-regulates quantity”	2’-3’-cGAMP(2-)	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	83
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1071718	NC_000006.11:g.(?72596727)(74363609_?)del	Pathogenic

SpliceAI

1497 predictions. Top by Δscore:

Variant	Effect	Δscore
6:73413781:GCTGT:G	donor_gain	1.0000
6:73413782:C:G	donor_gain	1.0000
6:73413782:CTGT:C	donor_gain	1.0000
6:73413784:GT:G	donor_gain	1.0000
6:73413784:GTGTA:G	donor_loss	1.0000
6:73413785:TGTA:T	donor_loss	1.0000
6:73413786:G:GG	donor_gain	1.0000
6:73413787:TAGG:T	donor_loss	1.0000
6:73413968:A:AG	acceptor_gain	1.0000
6:73413969:G:GG	acceptor_gain	1.0000
6:73414543:TTTA:T	acceptor_loss	1.0000
6:73414544:TTA:T	acceptor_loss	1.0000
6:73414545:TA:T	acceptor_loss	1.0000
6:73414546:A:AG	acceptor_gain	1.0000
6:73414546:A:C	acceptor_loss	1.0000
6:73414547:G:GC	acceptor_gain	1.0000
6:73414682:GCAGG:G	donor_gain	1.0000
6:73414684:AGG:A	donor_gain	1.0000
6:73414685:GG:G	donor_gain	1.0000
6:73414685:GGG:G	donor_gain	1.0000
6:73414686:GG:G	donor_gain	1.0000
6:73414687:G:GC	donor_loss	1.0000
6:73414687:G:GG	donor_gain	1.0000
6:73414688:T:A	donor_loss	1.0000
6:73416204:G:GT	donor_gain	1.0000
6:73416214:G:GT	donor_gain	1.0000
6:73425576:TTCC:T	acceptor_loss	1.0000
6:73425577:TCCT:T	acceptor_loss	1.0000
6:73425578:CCT:C	acceptor_loss	1.0000
6:73425579:CTGTT:C	acceptor_loss	1.0000

AlphaMissense

3434 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:73428803:A:G	W375R	0.990
6:73428803:A:T	W375R	0.990
6:73425433:A:G	W455R	0.986
6:73425433:A:T	W455R	0.986
6:73445727:A:C	F226L	0.986
6:73445727:A:T	F226L	0.986
6:73445729:A:G	F226L	0.986
6:73440335:A:G	W330R	0.985
6:73440335:A:T	W330R	0.985
6:73425344:A:C	F484L	0.984
6:73425344:A:T	F484L	0.984
6:73425346:A:G	F484L	0.984
6:73425431:C:A	W455C	0.981
6:73425431:C:G	W455C	0.981
6:73428789:G:C	F379L	0.981
6:73428789:G:T	F379L	0.981
6:73428791:A:G	F379L	0.981
6:73425578:C:A	R406S	0.979
6:73425578:C:G	R406S	0.979
6:73428801:C:A	W375C	0.976
6:73428801:C:G	W375C	0.976
6:73445610:A:C	F265L	0.975
6:73445610:A:T	F265L	0.975
6:73445612:A:G	F265L	0.975
6:73428799:C:G	R376P	0.974
6:73425479:T:A	K439N	0.973
6:73425479:T:G	K439N	0.973
6:73425404:A:C	F464L	0.972
6:73425404:A:T	F464L	0.972
6:73425406:A:G	F464L	0.972

dbSNP variants (sampled 300 via entrez): RS1000039180 (6:73442523 C>T), RS1000039962 (6:73425916 G>C), RS1000145966 (6:73427092 T>A,C,G), RS1000175681 (6:73425686 A>C), RS1000306634 (6:73438992 C>T), RS1000379680 (6:73438706 A>G), RS1000380333 (6:73430058 TAAA>T,TAAAA), RS1000482968 (6:73436631 C>T), RS1000643182 (6:73443898 C>G), RS1000647529 (6:73430469 G>C), RS1000909876 (6:73444162 G>C), RS1000997305 (6:73444002 A>C), RS1001030777 (6:73451278 T>C), RS1001039428 (6:73427076 C>T), RS1001060376 (6:73451062 G>A,T)

Disease associations

OMIM: gene MIM:613973 | disease phenotypes: MIM:604369

GenCC curated gene-disease

Mondo (1): Salla disease (MONDO:0011449)

Orphanet (2): Salla disease (Orphanet:309334), Free sialic acid storage disease (Orphanet:834)

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4105728 (SINGLE PROTEIN), CHEMBL6195545 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 62,750 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1535	HYDROXYCHLOROQUINE	4	42,638
CHEMBL7568	QUINACRINE	4	20,112

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Cyclic GMP-AMP turnover

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
compound 20 [PMID: 37666112]	Inhibition	5.64	pIC50
baicalin	Inhibition	5.4	pIC50
PF‐06928215	Inhibition	5.31	pIC50

Binding affinities (BindingDB)

110 measured of 156 human assays (156 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(S)-2-amino-1-(6,7-dichloro-1-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3- b]indol-2-yl)ethan-1-one	IC50	17.8 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
(S)-1-(6,7-dichloro-1-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)- 2-hydroxyethan-1-one -	IC50	19 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
(S)-1-(6,7-dichloro-1-methyl-1,3,4,5-tetrahydro-2H- pyrido[4,3-b]indol-2-yl)-2-hydroxyethan-1-one -	IC50	19 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
WO-2020/186027, Compound 67	IC50	27.3 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
(S)-(6,7-dichloro-1-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(5-(2- hydroxyethoxy)pyrimidin-2-yl)methanone	IC50	32 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
(S)-2-amino-1-(7,8-dichloro-1-methyl-3,4-dihydropyrazino[1,2-b]indazol- 2(1H)-yl)ethan-1-one	IC50	33.1 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
(S)-2-amino-1-(7,8-dichloro-1-methyl-3,4- dihydropyrazino[1,2-b]indazol-2(1H)-yl)ethan-1-one	IC50	33.1 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
(S)-(6,7-dichloro-1-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(5- methoxypyrimidin-2-yl)methanone	IC50	37.4 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
2-amino-1-(6,7-dichloro-1-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3- b]indol-2-yl)ethan-1-one	IC50	37.7 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
(6,7-dichloro-9-methoxy-1-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2- yl)(5-methoxypyrimidin-2-yl)methanone	IC50	45.5 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
(6,7-dichloro-1-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(5-((2- (dimethylamino)ethyl)(methyl)amino)pyrimidin-2-yl)methanone	IC50	50.1 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
(6,7-dichloro-1-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(5- (methylamino)pyrimidin-2-yl)methanone	IC50	51.4 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
(6,7-dichloro-1-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(5-(4- methylpiperazin-1-yl)pyrimidin-2-yl)methanone	IC50	52 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
(S)-1-(7,8-dichloro-1-methyl-10-(1-methyl-1H-pyrazol-3-yl)-3,4- dihydropyrazino[1,2-b]indazol-2(1H)-yl)-2-hydroxyethan-1-one	IC50	59.9 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
(6,7-dichloro-1-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(5- morpholinopyrimidin-2-yl)methanon	IC50	68.5 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
(6,7-dichloro-1-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(5- methoxypyrimidin-2-yl)methanone	IC50	69.2 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
(S)-(7,8-dichloro-1-methyl-3,4-dihydropyrazino[1,2-b]indazol-2(1H)-yl)(5- methoxypyrimidin-2-yl)methanone	IC50	71.5 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
(6,7-dichloro-1-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(4-(2- hydroxyethoxy)pyrimidin-2-yl)methanone	IC50	78.7 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
(S)-1-(7,8-dichloro-1-methyl-3,4-dihydropyrazino[1,2-b]indazol-2(1H)-yl)-2- hydroxyethan-1-one	IC50	82.8 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
(S)-1-(7,8-dichloro-1-methyl-3,4-dihydropyrazino[1,2- b]indazol-2(1H)-yl)-2-hydroxyethan-1-one	IC50	82.8 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
(6,7-dichloro-1-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(5-((S)- 7,7-difluorohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyrimidin-2- yl)methanone	IC50	89.5 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
(S)-(6,7-dichloro-1-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(5-(2- methoxyethoxy)pyrimidin-2-yl)methanone	IC50	90.4 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
(6,7-dichloro-1-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(4- methoxypyrimidin-2-yl)methanone	IC50	94.5 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
2-amino-1-(6,7-dichloro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2- yl)ethan-1-one	IC50	95 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
(6,7-dichloro-1-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(5-(4- (oxetan-3-yl)piperazin-1-yl)pyrimidin-2-yl)methanone	IC50	102 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
(6,7-dichloro-1-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(4-(2- (dimethylamino)ethoxy)pyrimidin-2-yl)methanone	IC50	110 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
(6,7-dichloro-1,9-dimethyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(5- methoxypyrimidin-2-yl)methanone	IC50	115 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
(6,7-dichloro-9-(1-methyl-1H-pyrazol-3-yl)-1,3,4,5-tetrahydro-2H-pyrido[4,3- b]indol-2-yl)(5-methoxypyrimidin-2-yl)methanone	IC50	133 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
N-(2-methoxycyclohexyl)-5-methyl-7-oxo-3-phenyl-2-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-pyrazolo[1,5-a]pyrimidine-6-carboxamide	IC50	135 nM	US-10738056: Pyrazolopyrimidinone compounds and uses thereof
5-methyl-6-(3-oxo-1H-2-benzofuran-1-yl)-3-phenyl-2-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-pyrazolo[1,5-a]pyrimidin-7-one	IC50	135 nM	US-10738056: Pyrazolopyrimidinone compounds and uses thereof
5-methyl-3-phenyl-6-[5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-1,3,4-oxadiazol-2-yl]-2-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-pyrazolo[1,5-a]pyrimidin-7-one	IC50	135 nM	US-10738056: Pyrazolopyrimidinone compounds and uses thereof
5-methyl-6-[5-(oxolan-3-yl)-1,3,4-oxadiazol-2-yl]-3-phenyl-2-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-pyrazolo[1,5-a]pyrimidin-7-one	IC50	135 nM	US-10738056: Pyrazolopyrimidinone compounds and uses thereof
5-methyl-6-[5-(oxan-3-yl)-1,3,4-oxadiazol-2-yl]-3-phenyl-2-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-pyrazolo[1,5-a]pyrimidin-7-one	IC50	135 nM	US-10738056: Pyrazolopyrimidinone compounds and uses thereof
tert-butyl 3-[5-[5-methyl-7-oxo-3-phenyl-2-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-pyrazolo[1,5-a]pyrimidin-6-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate	IC50	135 nM	US-10738056: Pyrazolopyrimidinone compounds and uses thereof
5-methyl-3-phenyl-6-(5-piperidin-3-yl-1,3,4-oxadiazol-2-yl)-2-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-pyrazolo[1,5-a]pyrimidin-7-one	IC50	135 nM	US-10738056: Pyrazolopyrimidinone compounds and uses thereof
benzyl 3-[5-[5-methyl-7-oxo-3-phenyl-2-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-pyrazolo[1,5-a]pyrimidin-6-yl]-1,3,4-oxadiazol-2-yl]morpholine-4-carboxylate	IC50	135 nM	US-10738056: Pyrazolopyrimidinone compounds and uses thereof
6-[5-(1-acetylpiperidin-3-yl)-1,3,4-oxadiazol-2-yl]-5-methyl-3-phenyl-2-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-pyrazolo[1,5-a]pyrimidin-7-one	IC50	135 nM	US-10738056: Pyrazolopyrimidinone compounds and uses thereof
5-methyl-6-(5-morpholin-3-yl-1,3,4-oxadiazol-2-yl)-3-phenyl-2-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-pyrazolo[1,5-a]pyrimidin-7-one	IC50	135 nM	US-10738056: Pyrazolopyrimidinone compounds and uses thereof
tert-butyl 2-[5-[5-methyl-7-oxo-3-phenyl-2-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-pyrazolo[1,5-a]pyrimidin-6-yl]-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate	IC50	135 nM	US-10738056: Pyrazolopyrimidinone compounds and uses thereof
5-methyl-6-[5-(3-methyloxan-3-yl)-1,3,4-oxadiazol-2-yl]-3-phenyl-2-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-pyrazolo[1,5-a]pyrimidin-7-one	IC50	135 nM	US-10738056: Pyrazolopyrimidinone compounds and uses thereof
6-[5-[2-(methoxymethyl)pyrrolidin-1-yl]-1,3,4-oxadiazol-2-yl]-5-methyl-3-phenyl-2-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-pyrazolo[1,5-a]pyrimidin-7-one	IC50	135 nM	US-10738056: Pyrazolopyrimidinone compounds and uses thereof
6-[5-[2-(methoxymethyl)piperidin-1-yl]-1,3,4-oxadiazol-2-yl]-5-methyl-3-phenyl-2-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-pyrazolo[1,5-a]pyrimidin-7-one	IC50	135 nM	US-10738056: Pyrazolopyrimidinone compounds and uses thereof
6-[5-[2-(2-aminoethyl)piperidin-1-yl]-1,3,4-oxadiazol-2-yl]-5-methyl-3-phenyl-2-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-pyrazolo[1,5-a]pyrimidin-7-one	IC50	135 nM	US-10738056: Pyrazolopyrimidinone compounds and uses thereof
6-[5-[3-(aminomethyl)piperidin-1-yl]-1,3,4-oxadiazol-2-yl]-5-methyl-3-phenyl-2-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-pyrazolo[1,5-a]pyrimidin-7-one	IC50	135 nM	US-10738056: Pyrazolopyrimidinone compounds and uses thereof
6-[5-(3-hydroxypiperidin-1-yl)-1,3,4-oxadiazol-2-yl]-5-methyl-3-phenyl-2-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-pyrazolo[1,5-a]pyrimidin-7-one	IC50	135 nM	US-10738056: Pyrazolopyrimidinone compounds and uses thereof
6-[5-(4-acetylmorpholin-3-yl)-1,3,4-oxadiazol-2-yl]-5-methyl-3-phenyl-2-(trifluoromethyl)-1H-pyrazolo[1,5-a]pyrimidin-7-one	IC50	135 nM	US-10738056: Pyrazolopyrimidinone compounds and uses thereof
WO-2019/153002, TDI-005685	IC50	146 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
(6,7-dichloro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(5-((2- hydroxyethyl)(methyl)amino)pyrimidin-2-yl)methanone	IC50	156 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
(6,7-dichloro-9-(pyrimidin-5-yl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2- yl)(5-methoxypyrimidin-2-yl)methanone	IC50	156 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS
(6,7-dichloro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(5-((2- hydroxyethyl)amino)pyrimidin-2-yl)methanone	IC50	174 nM	US-20250179079: HEXAHYDROPYRIDO[4,3-B]INDOLYL KETONE DERIVATIVES USEFUL AS CGAS MODULATORS

ChEMBL bioactivities

315 potent at pChembl≥5 of 359 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.36	IC50	0.44	nM	CHEMBL5612485
9.00	IC50	1	nM	CHEMBL5612485
8.82	IC50	1.5	nM	CHEMBL5614320
8.70	IC50	2	nM	CHEMBL5620249
8.68	IC50	2.1	nM	CHEMBL5612485
8.68	IC50	2.1	nM	CHEMBL5641551
8.62	IC50	2.4	nM	CHEMBL5612416
8.57	IC50	2.7	nM	CHEMBL5614320
8.55	IC50	2.8	nM	CHEMBL5614182
8.52	IC50	3	nM	CHEMBL5613252
8.51	IC50	3.1	nM	CHEMBL5613252
8.46	IC50	3.5	nM	CHEMBL5613252
8.40	IC50	4	nM	MANGOSTIN
8.40	IC50	4	nM	CHEMBL5614320
8.35	IC50	4.5	nM	CHEMBL5612416
8.30	IC50	5	nM	CHEMBL5614182
8.30	IC50	5	nM	CHEMBL5619434
8.22	IC50	6	nM	CHEMBL5573599
8.15	IC50	7	nM	CHEMBL5619280
8.14	IC50	7.2	nM	CHEMBL5613515
8.10	IC50	8	nM	CHEMBL5613515
8.10	IC50	8	nM	CHEMBL5620136
8.10	IC50	8	nM	CHEMBL5618800
8.10	IC50	8	nM	CHEMBL5618706
8.00	IC50	10	nM	CHEMBL4448176
7.99	IC50	10.2	nM	CHEMBL4448176
7.89	IC50	13	nM	CHEMBL5613515
7.85	IC50	14	nM	CHEMBL5082056
7.85	IC50	14	nM	CHEMBL5174318
7.85	IC50	14	nM	CHEMBL5613451
7.77	IC50	17	nM	CHEMBL5612416
7.57	IC50	27	nM	CHEMBL5081956
7.57	IC50	27	nM	CHEMBL6145827
7.56	IC50	27.5	nM	CHEMBL5081956
7.52	IC50	30	nM	CHEMBL5203275
7.50	IC50	32	nM	CHEMBL6142403
7.47	IC50	34	nM	CHEMBL5613424
7.44	IC50	36	nM	CHEMBL6132702
7.43	IC50	37	nM	CHEMBL6148998
7.41	IC50	39	nM	CHEMBL5613451
7.29	IC50	51	nM	CHEMBL5082056
7.28	Kd	53	nM	CHEMBL5082056
7.27	IC50	54	nM	CHEMBL5612358
7.22	IC50	60	nM	BX-795
7.22	IC50	60	nM	CHEMBL6142403
7.16	IC50	70	nM	CHEMBL5206813
7.16	IC50	70	nM	CHEMBL5574373
7.16	IC50	69	nM	CHEMBL6102012
7.06	IC50	87	nM	CHEMBL5613451
7.00	IC50	100	nM	CHEMBL5207488

PubChem BioAssay actives

153 with measured affinity, of 336 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(1R,12S,14S,38S)-28,28-difluoro-38-methyl-35-oxo-11,18,30-trioxa-2,9,15,26,36,41-hexazaoctacyclo[34.2.2.112,15.116,27.02,10.03,8.017,25.019,24]dotetraconta-3,5,7,9,16(41),17(25),19,21,23,26-decaene-14-carboxylic acid	2127433: Inhibition of cGAS in human THP-1 cells expressed in baculovirus infected insect cells incubated for 18 hrs by Lucia luciferase reporter assay	ic50	0.0004	uM
(1S,12S,14S,37S)-21-chloro-28,28-difluoro-37-methyl-34-oxo-11,18,32-trioxa-2,9,15,26,35,40-hexazaoctacyclo[33.2.2.112,15.116,27.02,10.03,8.017,25.019,24]hentetraconta-3,5,7,9,16(40),17(25),19(24),20,22,26-decaene-14-carboxylic acid	2127433: Inhibition of cGAS in human THP-1 cells expressed in baculovirus infected insect cells incubated for 18 hrs by Lucia luciferase reporter assay	ic50	0.0015	uM
2-[[(1S)-7,8-dichloro-1-methyl-2-oxo-3,4,5,6-tetrahydro-1H-azepino[4,5-b]indol-10-yl]oxy]acetonitrile	2131008: Inhibition of full length his-tagged human recombinant cGAS extracted from Escherichia coli BL21 (DE3) incubated for 3 hrs by rapidfire 365 mass spectrometry analysis	ic50	0.0020	uM
1-(7-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)-2-phenylethane-1,2-dione	2139956: Inhibition of cyclic GMP-AMP synthase (unknown origin)	ic50	0.0021	uM
(1S,12S,14S,37S)-6,21-dichloro-37-methyl-34-oxo-11,18,30-trioxa-2,9,15,26,35,40-hexazaoctacyclo[33.2.2.112,15.116,27.02,10.03,8.017,25.019,24]hentetraconta-3(8),4,6,9,16(40),17(25),19(24),20,22,26-decaene-14-carboxylic acid	2127433: Inhibition of cGAS in human THP-1 cells expressed in baculovirus infected insect cells incubated for 18 hrs by Lucia luciferase reporter assay	ic50	0.0024	uM
(1S,12S,14S,37S)-14-acetyl-6-chloro-37-methyl-11,18,30-trioxa-2,9,15,26,35,40-hexazaoctacyclo[33.2.2.112,15.116,27.02,10.03,8.017,25.019,24]hentetraconta-3(8),4,6,9,16(40),17(25),19,21,23,26-decaen-34-one	2127432: Inhibition of N-terminal 6His-SUMO tagged human cGAS (1 to 522 residues) extracted from Escherichia coli BL21(DE3)pLysS cells using GTP/ATP as substrate by measuring cGAMP production incubated for 90 mins in presence of 45 base pair DNA by mass spectrometric analysis	ic50	0.0028	uM
(1S,12S,14S,37S)-6-chloro-28,28-difluoro-37-methyl-34-oxo-11,18,29-trioxa-2,9,15,26,35,40-hexazaoctacyclo[33.2.2.112,15.116,27.02,10.03,8.017,25.019,24]hentetraconta-3(8),4,6,9,16(40),17(25),19,21,23,26-decaene-14-carboxylic acid	2127435: Inhibition of cGAS in dsDNA stimulated human Whole blood cell by measuring IFNalpha-2a production incubated for 60 mins followed by addition of double stranded DNA measured after 1350 mins by microplate reader assay	ic50	0.0030	uM
1,3,6-trihydroxy-7-methoxy-2,8-bis(3-methylbut-2-enyl)xanthen-9-one	1575519: Binding affinity to STING (unknown origin)	ic50	0.0040	uM
2-[7,8-dichloro-10-(2-methyltriazol-4-yl)-2-oxo-3,4,5,6-tetrahydro-1H-azepino[4,5-b]indol-5-yl]acetic acid	2131008: Inhibition of full length his-tagged human recombinant cGAS extracted from Escherichia coli BL21 (DE3) incubated for 3 hrs by rapidfire 365 mass spectrometry analysis	ic50	0.0050	uM
1-[(3S)-7,8-dichloro-5-[1-(difluoromethyl)pyrazol-3-yl]spiro[1,2,4,9-tetrahydrocarbazole-3,3’-pyrrolidine]-1’-yl]-2-hydroxyethanone	2105367: Inhibition of full length recombinant human cGAS expressed in Escherichia coli BL21 (DE3) incubated for 7 hrs by Kinase-glo max luminescent kinase assay	ic50	0.0060	uM
(1S)-7,8-dichloro-10-(3-hydroxypropoxy)-1-methyl-3,4,5,6-tetrahydro-1H-azepino[4,5-b]indol-2-one	2131008: Inhibition of full length his-tagged human recombinant cGAS extracted from Escherichia coli BL21 (DE3) incubated for 3 hrs by rapidfire 365 mass spectrometry analysis	ic50	0.0070	uM
(1S,12S,14S,37S)-28,28,33,33-tetrafluoro-37-methyl-34-oxo-11,18-dioxa-2,9,15,26,35,40-hexazaoctacyclo[33.2.2.112,15.116,27.02,10.03,8.017,25.019,24]hentetraconta-3,5,7,9,16(40),17(25),19,21,23,26-decaene-14-carboxylic acid	2127432: Inhibition of N-terminal 6His-SUMO tagged human cGAS (1 to 522 residues) extracted from Escherichia coli BL21(DE3)pLysS cells using GTP/ATP as substrate by measuring cGAMP production incubated for 90 mins in presence of 45 base pair DNA by mass spectrometric analysis	ic50	0.0072	uM
(1S,5R)-7,8-dichloro-10-(2-hydroxyethylamino)-5-(2-methoxyethyl)-1-methyl-3,4,5,6-tetrahydro-1H-azepino[4,5-b]indol-2-one	2131008: Inhibition of full length his-tagged human recombinant cGAS extracted from Escherichia coli BL21 (DE3) incubated for 3 hrs by rapidfire 365 mass spectrometry analysis	ic50	0.0080	uM
2-[(5R)-7,8-dichloro-5-(2,2-difluoropropyl)-2-oxo-3,4,5,6-tetrahydro-1H-azepino[4,5-b]indol-10-yl]acetonitrile	2131008: Inhibition of full length his-tagged human recombinant cGAS extracted from Escherichia coli BL21 (DE3) incubated for 3 hrs by rapidfire 365 mass spectrometry analysis	ic50	0.0080	uM
(1S)-7,8-dichloro-10-(3-methoxypropoxy)-1-methyl-3,4,5,6-tetrahydro-1H-azepino[4,5-b]indol-2-one	2131008: Inhibition of full length his-tagged human recombinant cGAS extracted from Escherichia coli BL21 (DE3) incubated for 3 hrs by rapidfire 365 mass spectrometry analysis	ic50	0.0080	uM
1-[9-(6-amino-3-pyridinyl)-6,7-dichloro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl]-2-hydroxyethanone	1817425: Inhibition of human cGAS	ic50	0.0100	uM
1-[6,7-dichloro-9-(1-methylpyrazol-4-yl)-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl]-2-hydroxyethanone	1854205: Inhibition of human cGAS	ic50	0.0140	uM
1-[6,7-dichloro-9-(1-methylpyrazol-3-yl)-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl]-2-hydroxyethanone	1817425: Inhibition of human cGAS	ic50	0.0140	uM
(1R,12S,14S,37R)-6-chloro-37-methyl-34-oxo-11,18,30-trioxa-2,9,15,26,35,40-hexazaoctacyclo[33.2.2.112,15.116,27.02,10.03,8.017,25.019,24]hentetraconta-3(8),4,6,9,16(40),17(25),19,21,23,26-decaene-14-carboxylic acid	2127432: Inhibition of N-terminal 6His-SUMO tagged human cGAS (1 to 522 residues) extracted from Escherichia coli BL21(DE3)pLysS cells using GTP/ATP as substrate by measuring cGAMP production incubated for 90 mins in presence of 45 base pair DNA by mass spectrometric analysis	ic50	0.0140	uM
1-[6,7-dichloro-9-(1H-pyrazol-4-yl)-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl]-2-hydroxyethanone	1817425: Inhibition of human cGAS	ic50	0.0270	uM
3-(4-hydroxy-2-piperidin-1-yl-1,3-thiazol-5-yl)indol-2-one	1854203: Inhibition of cGAS (unknown origin)	ic50	0.0300	uM
(1S,12S,14S,37S)-33,37-dimethyl-34-oxo-11,18-dioxa-2,9,15,26,33,35,40-heptazaoctacyclo[33.2.2.112,15.116,27.02,10.03,8.017,25.019,24]hentetraconta-3,5,7,9,16(40),17(25),19,21,23,26-decaene-14-carboxylic acid	2127432: Inhibition of N-terminal 6His-SUMO tagged human cGAS (1 to 522 residues) extracted from Escherichia coli BL21(DE3)pLysS cells using GTP/ATP as substrate by measuring cGAMP production incubated for 90 mins in presence of 45 base pair DNA by mass spectrometric analysis	ic50	0.0340	uM
(1R,12S,14S,37R)-37-methyl-34-oxo-11,18,33-trioxa-2,9,15,26,35,40-hexazaoctacyclo[33.2.2.112,15.116,27.02,10.03,8.017,25.019,24]hentetraconta-3,5,7,9,16(40),17(25),19,21,23,26-decaene-14-carboxylic acid	2127432: Inhibition of N-terminal 6His-SUMO tagged human cGAS (1 to 522 residues) extracted from Escherichia coli BL21(DE3)pLysS cells using GTP/ATP as substrate by measuring cGAMP production incubated for 90 mins in presence of 45 base pair DNA by mass spectrometric analysis	ic50	0.0540	uM
N-[3-[[5-iodo-4-[3-(thiophene-2-carbonylamino)propylamino]pyrimidin-2-yl]amino]phenyl]pyrrolidine-1-carboxamide	1475999: Inhibition of cGAS in human THP1 cells assessed as reduction in salmon sperm dsDNA-induced IFN-beta expression preincubated for 1 hr followed by dsDNA stimulation for 12 hrs by luciferase reporter gene assay	ic50	0.0600	uM
1-[7,8-dichloro-5-[1-(difluoromethyl)pyrazol-3-yl]spiro[1,2,4,9-tetrahydrocarbazole-3,3’-pyrrolidine]-1’-yl]-2-hydroxyethanone	2105367: Inhibition of full length recombinant human cGAS expressed in Escherichia coli BL21 (DE3) incubated for 7 hrs by Kinase-glo max luminescent kinase assay	ic50	0.0700	uM
2-(4-chloronaphthalen-1-yl)oxy-N-(3-hydroxy-2-pyridinyl)acetamide	1854203: Inhibition of cGAS (unknown origin)	ic50	0.0700	uM
4-nitro-N-(4-phenyl-2-pyridinyl)-1H-pyrazole-5-carboxamide	1846693: Inhibition of full length human cGAS expressed in Escherichia coli BL21 (DE3) incubated for 2 hrs in presence of ATP by RF-MS analysis	ic50	0.1000	uM
(1R,12S,14S,37R)-28,28-difluoro-7,37-dimethyl-34-oxo-11,18-dioxa-2,9,15,26,35,40-hexazaoctacyclo[33.2.2.112,15.116,27.02,10.03,8.017,25.019,24]hentetraconta-3,5,7,9,16(40),17(25),19,21,23,26-decaene-14-carboxylic acid	2127432: Inhibition of N-terminal 6His-SUMO tagged human cGAS (1 to 522 residues) extracted from Escherichia coli BL21(DE3)pLysS cells using GTP/ATP as substrate by measuring cGAMP production incubated for 90 mins in presence of 45 base pair DNA by mass spectrometric analysis	ic50	0.1000	uM
2-(4,5-dichloro-1H-benzimidazol-2-yl)-5-methyl-4-(3-oxo-1H-2-benzofuran-1-yl)-1H-pyrazol-3-one	1854203: Inhibition of cGAS (unknown origin)	ic50	0.1100	uM
2-(6,7-dichloro-1H-indol-2-yl)-5-methyl-4-(3-oxo-1H-2-benzofuran-1-yl)-1H-pyrazol-3-one	2105418: Inhibition of human cGas incubated for 120 mins	ic50	0.1100	uM
cis-(1R,2S)-2-[(7-oxo-5-phenyl-1H-pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]cyclohexane-1-carboxylic acid	1475996: Binding affinity to human cGAS (2 to 522 residues) expressed in Sf9 insect cells by surface plasmon resonance assay	kd	0.2000	uM
cis-(1S,2R)-2-[(7-oxo-5-phenyl-3a,4-dihydro-3H-pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]cyclohexane-1-carboxylic acid	1854215: Binding affinity to cGAS (unknown origin) assessed as dissociation constant	kd	0.2000	uM
methyl 4-amino-6-(3,5-difluoro-4-iodoanilino)-1,3,5-triazine-2-carboxylate	1817424: Inhibition of human cGAS assessed as reduction in 2,3-cGAMP synthesis by measuring ATP consumption incubated for 20 mins by Kinase Glo luminescence assay	ic50	0.2400	uM
7-chloro-4-imidazol-1-yl-6-methoxyquinoline	1846702: Inhibition of full-length human cGAS by fluorescence polarization	ic50	0.3910	uM
7-(3-chlorophenyl)-6-methyl-8-oxo-3-phenyl-5H-imidazo[1,2-b]pyridazine-2-carbonitrile	1846702: Inhibition of full-length human cGAS by fluorescence polarization	ic50	1.0000	uM
N-(5-chloro-2-pyridinyl)-4-nitro-1H-pyrazole-5-carboxamide	1854205: Inhibition of human cGAS	ic50	1.0300	uM
1-(6,8-dichloro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-2-methoxyethanone	1854204: Inhibition of human (His6)-SUMO tagged cGAS expressed in Escherichia coli BL21-codonPlus(DE3)-RIL by ATP-biofluorescence assay	ic50	1.0400	uM
[2-[6,7-dichloro-9b-(4-chloro-2-formylanilino)-3,4-dihydro-1H-pyrido[4,3-b]indol-2-yl]-2-oxoethyl] acetate	1817407: Inhibition of human cGAS expressed in THP1-Dual cells transfected with HT-DNA assessed as suppression of lipofectamine 2000:ds-DNA complex induced activation of cGAS incubated for 1 hr by Quanti-luc reagent based assay	ic50	1.1400	uM
2-amino-N-[2-[6,7-dichloro-9-(1-methylpyrazol-3-yl)-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl]-2-oxoethyl]acetamide	1817407: Inhibition of human cGAS expressed in THP1-Dual cells transfected with HT-DNA assessed as suppression of lipofectamine 2000:ds-DNA complex induced activation of cGAS incubated for 1 hr by Quanti-luc reagent based assay	ic50	1.3800	uM
2-chloro-N-[4-(1H-indol-3-yl)-1,3-thiazol-2-yl]acetamide	1854203: Inhibition of cGAS (unknown origin)	ic50	1.4000	uM
2-amino-1-[6,7-dichloro-9-(1-methylpyrazol-3-yl)-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl]ethanone	1817407: Inhibition of human cGAS expressed in THP1-Dual cells transfected with HT-DNA assessed as suppression of lipofectamine 2000:ds-DNA complex induced activation of cGAS incubated for 1 hr by Quanti-luc reagent based assay	ic50	1.8700	uM
2-(1H-benzimidazol-2-yl)-5-methyl-4-(3-oxo-1H-2-benzofuran-1-yl)-1H-pyrazol-3-one	1854203: Inhibition of cGAS (unknown origin)	ic50	1.8900	uM
N-[(2S)-1-hydroxypropan-2-yl]-7-oxo-5-phenyl-1H-pyrazolo[1,5-a]pyrimidine-3-carboxamide	1475996: Binding affinity to human cGAS (2 to 522 residues) expressed in Sf9 insect cells by surface plasmon resonance assay	kd	2.7000	uM
[2-[6,7-dichloro-9b-[2-formyl-4-(trifluoromethyl)anilino]-3,4-dihydro-1H-pyrido[4,3-b]indol-2-yl]-2-oxoethyl] acetate	1817407: Inhibition of human cGAS expressed in THP1-Dual cells transfected with HT-DNA assessed as suppression of lipofectamine 2000:ds-DNA complex induced activation of cGAS incubated for 1 hr by Quanti-luc reagent based assay	ic50	2.7200	uM
[2-[6,7-dichloro-9b-(3-chloro-2-formylanilino)-3,4-dihydro-1H-pyrido[4,3-b]indol-2-yl]-2-oxoethyl] acetate	1817407: Inhibition of human cGAS expressed in THP1-Dual cells transfected with HT-DNA assessed as suppression of lipofectamine 2000:ds-DNA complex induced activation of cGAS incubated for 1 hr by Quanti-luc reagent based assay	ic50	2.8700	uM
1-[9b-[3,5-bis(trifluoromethyl)anilino]-6,7-dichloro-3,4-dihydro-1H-pyrido[4,3-b]indol-2-yl]-2-hydroxyethanone	1817407: Inhibition of human cGAS expressed in THP1-Dual cells transfected with HT-DNA assessed as suppression of lipofectamine 2000:ds-DNA complex induced activation of cGAS incubated for 1 hr by Quanti-luc reagent based assay	ic50	3.1200	uM
[2-[9b-[3,5-bis(trifluoromethyl)anilino]-6,7-dichloro-3,4-dihydro-1H-pyrido[4,3-b]indol-2-yl]-2-oxoethyl] acetate	1817407: Inhibition of human cGAS expressed in THP1-Dual cells transfected with HT-DNA assessed as suppression of lipofectamine 2000:ds-DNA complex induced activation of cGAS incubated for 1 hr by Quanti-luc reagent based assay	ic50	3.2300	uM
2-amino-1-[7,8-dichloro-5-[2-(trifluoromethyl)-4-pyridinyl]spiro[1,2,4,9-tetrahydrocarbazole-3,3’-pyrrolidine]-1’-yl]ethanone	2105359: Inhibition of cGAS in human THP1-Dual cells preincubated for 1 hr followed by cGAMP addition and measured after 24 hrs by luminescence based QUANTI-Luc assay	ic50	3.4100	uM
1-[6,7-dichloro-9b-(1H-indol-3-yl)-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indol-2-yl]-2-hydroxyethanone	1817407: Inhibition of human cGAS expressed in THP1-Dual cells transfected with HT-DNA assessed as suppression of lipofectamine 2000:ds-DNA complex induced activation of cGAS incubated for 1 hr by Quanti-luc reagent based assay	ic50	4.0700	uM
1-[7,8-dichloro-5-[2-(trifluoromethyl)pyrimidin-4-yl]spiro[1,2,4,9-tetrahydrocarbazole-3,3’-pyrrolidine]-1’-yl]-2-hydroxyethanone	2105359: Inhibition of cGAS in human THP1-Dual cells preincubated for 1 hr followed by cGAMP addition and measured after 24 hrs by luminescence based QUANTI-Luc assay	ic50	4.2600	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
entinostat	increases expression, affects cotreatment	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Tobacco Smoke Pollution	increases expression	2
aristolochic acid I	increases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
RU.521	decreases reaction, increases expression	1
bisphenol A	decreases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
butyraldehyde	increases expression	1
beryllium sulfate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
cyanoginosin LR	affects localization, decreases reaction, affects binding, increases reaction, increases expression	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
2-(2’-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)biphenyl-3-yloxy)acetic acid	decreases reaction, increases expression	1
(+)-JQ1 compound	decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Air Pollutants	increases abundance, increases expression	1
Cadmium	increases expression	1
Cisplatin	increases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Drugs, Chinese Herbal	increases expression	1
Estradiol	increases expression	1
Lipopolysaccharides	increases expression, decreases reaction	1
Methyl Methanesulfonate	increases expression	1
Naphthoquinones	increases expression	1

ChEMBL screening assays

94 unique, capped per target: 92 binding, 2 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4031179	Binding	Binding affinity to human cGAS (2 to 522 residues) expressed in Sf9 insect cells by surface plasmon resonance assay	Discovery of PF-06928215 as a high affinity inhibitor of cGAS enabled by a novel fluorescence polarization assay. — PLoS One
CHEMBL4338389	ADMET	Substrate activity at recombinant full-length human CGAS expressed in Escherichia coli BL21 (DE3) assessed as cyclic dinucleotide formation by measuring reaction conversion at 1 mM incubated for 16 hrs in presence of GTP by HPLC-UV analysis	Enzymatic Preparation of 2’-5’,3’-5’-Cyclic Dinucleotides, Their Binding Properties to Stimulator of Interferon Genes Adaptor Protein, and Structure/Activity Correlations. — J Med Chem

Cellosaurus cell lines

7 cell lines: 5 cancer cell line, 1 hybrid cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A8AI	THP1-Dual KO-cGAS	Cancer cell line	Male
CVCL_E0A3	Ubigene HeLa CGAS KO	Cancer cell line	Female
CVCL_E1J3	HyCyte AC16 KO-hCGAS	Hybrid cell line
CVCL_E1LE	HyCyte HTR-8/SVneo KO-hCGAS	Transformed cell line	Sex unspecified
CVCL_F1TY	HyCyte THP-1 KO-hCGAS	Cancer cell line	Male
CVCL_SX38	HAP1 MB21D1 (-) 1	Cancer cell line	Male
CVCL_SX39	HAP1 MB21D1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project