Table 2 Mammalian STING variants and mutants

Mutation	Motif	Functional effect/ Disease association	Occurrence	References
S162A	ligand binding site	Reduce c-di-GMP binding Increase hSTING sensitivity to DMXAA	N/A	[53]
G230A	ligand binding site	Impair C-terminal binding to c-di-GMP	N/A	[104]
G230A-R293Q	ligand binding site	Double mutant Partially reduced IFN-β response to bacterial ligands	5.2% / 1000 human genome	[104]
R293Q	ligand binding site	Significantly reduced IFN-β response to bacterial ligands	1.5%/ 1000 human genome	[104]
R232H	ligand binding site	Partially reduced IFN-β response to c-di-GMP and complete loss of IFN response to other bacterial ligands	13.7% / 1000 human genome	[104]
R71H-G230A-R293Q (HAQ)	Recessive Null allele	Triple mutant Low intrinsic IFN-β/NF-κB promoter activity Homologous significant decrease STING expression and abolish IFN-I response to all STING ligands	20.4% / 1000 human genome	[104, 106, 110]
V155 M	Hydrophobic core, ligand binding site	SAVI, constitutive activation	Very rare	[39, 108]
N154S	Hydrophobic core, ligand binding site	SAVI, constitutive activation	Very rare	[39]
V147 L	Hydrophobic core, ligand binding site	SAVI, constitutive activation	Very rare	[39]
I200N	Interior STING promoter	Complete abolish STING activity, equivalent to I199N mSTING missense mutation, Goldenticket strain	N/A	[111]
G160E	Dimerisation domain	FCL, constitutive activation	Very rare	[105]
S366A (loss) or S366D (gain)	Ulk1/2 target phosphorylation site	Both loss-of-function (S366A) & gain-of-function (S366D) mutations block IRF3 binding	N/A	[102]

Single nucleotide polymorphisms of STING have been discovered in human and mouse which are implicated in dysregulation of type I interferon signalling and the proinflammatory innate immune response. STING mutations highlighted in green manifest as loss-of-function characteristics, mutations highlighted in red manifest as gain-of-function characteristics, and mutation in black lacks any gain-of-function or loss-of-function characteristic of STING. Gain-of-function mutations of V155 M, N154S and V147 L have been identified in human autoinflammatory disease called STING-associated vasculopathy with onset in infancy (SAVI), and substitution of G160E is the major cause of another human autoimmune disease known as familiar chilblain lupus (FCL). The most predominant loss-of-function STING mutant named HAQ is considered to compromise host innate response against infection, yet no clinical evidence is available for further discussion. Others STING mutations are experimentally created to study type I interferon signalling pathways, but they are potentially pathological

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