IRF9

Summary

IRF9 (interferon regulatory factor 9, HGNC:6131) is a protein-coding gene on chromosome 14q12, encoding Interferon regulatory factor 9 (Q00978). Transcription factor that plays an essential role in anti-viral immunity.

This gene encodes a member of the interferon regulatory factor (IRF) family, a group of transcription factors with diverse roles, including virus-mediated activation of interferon, and modulation of cell growth, differentiation, apoptosis, and immune system activity. Members of the IRF family are characterized by a conserved N-terminal DNA-binding domain containing tryptophan (W) repeats. Mutations in this gene result in Immunodeficiency 65.

Source: NCBI Gene 10379 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 65, susceptibility to viral infections (Moderate, ClinGen)
• Clinical variants (ClinVar): 273 total
• Phenotypes (HPO): 6
• Transcription factor: yes — 32 downstream targets (CollecTRI)
• MANE Select transcript: NM_006084

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6131
Approved symbol	IRF9
Name	interferon regulatory factor 9
Location	14q12
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000213928
Ensembl biotype	protein_coding
OMIM	147574
Entrez	10379

Gene structure

Transcript identifiers

Ensembl transcripts: 81 — 34 retained_intron, 33 protein_coding, 14 nonsense_mediated_decay

ENST00000324076, ENST00000396864, ENST00000557894, ENST00000559229, ENST00000559284, ENST00000559863, ENST00000560275, ENST00000560311, ENST00000560365, ENST00000560542, ENST00000560852, ENST00000561009, ENST00000561342, ENST00000561412, ENST00000561415, ENST00000698995, ENST00000698996, ENST00000698997, ENST00000698998, ENST00000699015, ENST00000699016, ENST00000699017, ENST00000699018, ENST00000699019, ENST00000699020, ENST00000699021, ENST00000699022, ENST00000699023, ENST00000699024, ENST00000699025, ENST00000699049, ENST00000699063, ENST00000699064, ENST00000699065, ENST00000699066, ENST00000699067, ENST00000699068, ENST00000699069, ENST00000699070, ENST00000699071, ENST00000699072, ENST00000699073, ENST00000699076, ENST00000699077, ENST00000699078, ENST00000699079, ENST00000699080, ENST00000699081, ENST00000699082, ENST00000699083, ENST00000699099, ENST00000699100, ENST00000699101, ENST00000699102, ENST00000699103, ENST00000699104, ENST00000699105, ENST00000699106, ENST00000699107, ENST00000699108, ENST00000699109, ENST00000699110, ENST00000699111, ENST00000699178, ENST00000699179, ENST00000699180, ENST00000699181, ENST00000699182, ENST00000699183, ENST00000699184, ENST00000907730, ENST00000907731, ENST00000907732, ENST00000907733, ENST00000907734, ENST00000907735, ENST00000907736, ENST00000907737, ENST00000965754, ENST00000965755, ENST00000965756

RefSeq mRNA: 4 — MANE Select: NM_006084 NM_001385400, NM_001385401, NM_001385402, NM_006084

CCDS: CCDS91853, CCDS91854, CCDS91855, CCDS9615

Canonical transcript exons

ENST00000396864 — 9 exons

Exon	Start	End
ENSE00001689462	24162966	24163149
ENSE00001788498	24166122	24166565
ENSE00003585433	24163878	24163959
ENSE00003596924	24164063	24164134
ENSE00003627295	24165847	24165962
ENSE00003646924	24163378	24163508
ENSE00003975243	24162144	24162324
ENSE00003975358	24164614	24164955
ENSE00003975443	24161265	24161338

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.09.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 47.9736 / max 913.1065, expressed in 1808 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
138996	46.8135	1805
138997	0.6140	307
138998	0.5462	312

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
spleen	UBERON:0002106	99.09	gold quality
granulocyte	CL:0000094	99.05	gold quality
vermiform appendix	UBERON:0001154	98.44	gold quality
lymph node	UBERON:0000029	98.43	gold quality
blood	UBERON:0000178	98.39	gold quality
gall bladder	UBERON:0002110	98.29	gold quality
metanephros cortex	UBERON:0010533	98.23	gold quality
right uterine tube	UBERON:0001302	98.17	gold quality
adenohypophysis	UBERON:0002196	97.89	gold quality
bone marrow	UBERON:0002371	97.79	gold quality
bone marrow cell	CL:0002092	97.78	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.72	gold quality
pituitary gland	UBERON:0000007	97.62	gold quality
prostate gland	UBERON:0002367	97.55	gold quality
small intestine Peyer’s patch	UBERON:0003454	97.54	gold quality
leukocyte	CL:0000738	97.53	gold quality
tibial nerve	UBERON:0001323	97.48	gold quality
monocyte	CL:0000576	97.44	gold quality
duodenum	UBERON:0002114	97.42	gold quality
left lobe of thyroid gland	UBERON:0001120	97.41	gold quality
small intestine	UBERON:0002108	97.40	gold quality
upper lobe of left lung	UBERON:0008952	97.40	gold quality
right lobe of thyroid gland	UBERON:0001119	97.37	gold quality
right adrenal gland	UBERON:0001233	97.28	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.25	gold quality
hypothalamus	UBERON:0001898	97.23	gold quality
thyroid gland	UBERON:0002046	97.21	gold quality
mucosa of stomach	UBERON:0001199	97.20	gold quality
right lobe of liver	UBERON:0001114	97.19	gold quality
amygdala	UBERON:0001876	97.18	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.76
E-GEOD-99795	no	42.48

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

32 targets.

Target	Regulation
ANKRD1
CCL19	Activation
CCND2	Repression
CDKN1A	Activation
CDKN1B	Activation
CXCL10	Activation
CXCL8	Repression
IFIT1
IFIT3	Unknown
IFNA1
IFNB1
IFNG
IFNL3
IL12A	Activation
IL27	Repression
INS
IRF7	Activation
IRF9
MIR342
MYOCD
NCAM1	Activation
OAS1
PDCD1
PML	Activation
RN5S1@
SLU7
SNCA
SP100	Activation
SST
STAT1	Activation

JASPAR motifs

Motif	Name	Family
MA0653.1	IRF9	Interferon-regulatory factors

JASPAR matrix evidence (PMIDs): PMID:21731497

Upstream regulators (CollecTRI, top): BRCA1, CEBPB, ERCC6, GLI2, IRF3, IRF9, KLF6, STAT1, STAT2

Literature-anchored findings (GeneRIF, showing 40)

• the IFN-activated ISGF3 transcription factor regulates transcription through contact with DRIP150 (PMID:12509459)
• IRF9 functions to recruit RNA polymerase II to the promoter of interferon-stimulated genes and requires histone deacetylases (PMID:15194680)
• the conserved DNA-binding domain of STAT2 has a role specific to the activity of ISGF3-independent STAT2-containing complexes (PMID:15668228)
• defects in ISGF3 can cause resistance to IFN-alpha(2a) treatment (PMID:15714000)
• GBF1 is recruited to the endogenous IRF-9 promoter, and interacts with C/EBP-beta, IL-1, and IL-6 (PMID:16318580)
• Pretreatment of Huh-7 cells with 0.5-1 mM H2O2 resulted in the suppression of the IFN-alpha-induced antiviral protein MxA and of IRF-9 mRNA expression. (PMID:16595158)
• Data reveal the existence of a collection of GAS-regulated target genes whose expression is interferon-inducible and independent of ISGF3 but highly dependent on the STAT2 DNA binding domain. (PMID:16689942)
• Results identify Viperin as a tightly regulated ISGF3 target gene, which is counter-regulated by PRDI-BF1. (PMID:16849320)
• Suggest that the JAK-STAT pathway may play a major role in mediating the effects of IFN-alpha against hepatitis b virus, and that ISGF3 might be a key factor. (PMID:17559358)
• These data define the role of the ISGF3 members in IFN-beta inhibitory signaling. (PMID:18370868)
• The data suggest that liberation of the IFNaR2-ICD by regulated proteolysis could trigger a novel mechanism for moving the transcription factor Stat2 to the nucleus. (PMID:18456457)
• a key factor for eliciting the antiproliferative activity of IFN-alpha in tumors (PMID:19752753)
• NOD1 can activate the ISGF3 signaling pathway that is usually associated with protection against viral infection to provide robust type I IFN-mediated protection from H. pylori and possibly other mucosal infections (PMID:20389019)
• STAT2 may interact with IRF-9 in a STAT1-independent manner. The complex STAT2/IRF-9 is the key factor mediating the expression of RIG-G gene regulated by IFN-alpha. (PMID:20403236)
• analysis of IFN-stimulated response elements (ISREs) that bind to both the IFN-stimulated gene factor 3 (ISGF3) as well as to IFN response factor 7 (IRF7) (PMID:20943654)
• Results suggest that the amount of cellular IRF9 is a crucial determinant for amplification of early dynamics of IFNalpha-mediated signal transduction. (PMID:20964804)
• Signals ensued by IFN-alpha and IL-4 induce cytoplasmic sequestration of IL-4-activated STAT6 and IFN-alpha-activated STAT2:p48 in B cells through the formation of pY-STAT6:pY-STAT2:p48 complex. (PMID:21268015)
• Western blot and electrophoretic mobility-shift assays identified the interferon-stimulated gene factor-3 (ISGF-3) components STAT1 and IRF-9 as the proximal targets of human herpesvirus 8 vIRF-2 activity. (PMID:21697347)
• HDAC1 and HDAC2 differentially modulate STAT activity in response to IFNalpha2: while they are required for the induction of ISGF3-responsive genes, they impair the transcription of STAT3-dependent genes. (PMID:21957129)
• The hepatitis C virus (HCV) non-structural 5A (NS5A) protein, which is known to modulate the IFN response, competes with IRF9 for CypA binding and can prevent the formation of IRF9-CypA complexes. (PMID:22902549)
• IL6 is an inducer of IRF9 expression in prostate cancer and a sensitizer for the antiproliferative effects of IFNalpha2. (PMID:23913484)
• IRF9 mediated myocardial reperfusion injury (PMID:25150882)
• STAT2 and IRF9 overexpression is sufficient to drive interferon-related DNA damage signature expression upon cell crowding. (PMID:25156627)
• DC-SIGN-induced ISGF3 by fucose-based PAMPs has an essential role in driving IL-27 and subsequent TFH polarization, which might be harnessed for vaccination design (PMID:25278262)
• IRF9 is a vascular injury-response molecule that promotes VSMC proliferation. IRF9 expression is upregulated during neointima formation. (PMID:25319116)
• U-ISGF3 induced by IFN-lambdas and -beta drives prolonged expression of a set of IFN-stimulated genes during HCV infection (PMID:26216956)
• Interferonstimulated gene factor 3 complex, which consists of STAT1, STAT2 and IRF9, is required for the induction of SAMHD1 expression by IFN-alpha in SMMC-7721 cells. (PMID:26397446)
• Recent studies have revealed a unique role for IRF9 as a conductor of the cellular responses to IFN-Is. Intriguingly, novel roles for IRF9 outside of the antiviral response are also being identified. (PMID:26987614)
• these findings identify miR-302d as a key regulator of type I IFN driven gene expression via its ability to target IRF9 and regulate ISG expression, underscoring the importance of non-coding RNA in regulating the IFN pathway in SLE. (PMID:28318807)
• PKV VP3 associated with STAT2 and IRF9, and interfered with the formation of the STAT2-IRF9 and STAT2-STAT2 complex. (PMID:28441586)
• Decreased IRF9 expression was accompanied by increased replication of hepatitis C virus and hepatitis E virus. (PMID:28442624)
• Surface features in the interacting domains of IRF9 and STAT2 have diverged to enable specific interaction between these family members and to enable the antiviral response. (PMID:29317535)
• Priming cells with IFNbeta synergistically enhances IL6 induction in response to treatments that activate NF-kappaB, in a process that depends upon the recruitment of STAT2, IRF9. (PMID:29581268)
• findings show that human IRF9- and ISGF3-dependent type I and III IFN responsive pathways are essential for controlling IAV. (PMID:30143481)
• this review outlines the structural basis of IRF9 that guides its regulation and interaction in antiviral immunity and other diseases (PMID:30147694)
• Thus after VHL inactivation, HIF induces ISGF3, which is reversed by the loss of secondary tumor suppressors, suggesting that this is a key negative feedback loop in clear cell renal cell carcinoma. (PMID:30355451)
• the type I IFN receptor signal elicits an increase in PD-L1 expression in lung cancer cells through IRF9-dependent and independent pathways. (PMID:30446226)
• Transcription factor STAT3 is activated upstream of IRF9 and binds to the IRF9 promoter in multicellular spheroids (MCS) of HCT116 colorectal carcinoma cells. STAT3 mediates expression of IRF9 and interferon stimulated genes. (PMID:30679726)
• The Measles Virus V Protein Binding Site to STAT2 Overlaps That of IRF9. (PMID:32581091)
• SARS-CoV-2 Spike Targets USP33-IRF9 Axis via Exosomal miR-148a to Activate Human Microglia. (PMID:33936086)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	irf9	ENSDARG00000016457
danio_rerio	irf4b	ENSDARG00000055374
mus_musculus	Irf9	ENSMUSG00000002325
rattus_norvegicus	Irf9	ENSRNOG00000019478

Paralogs (8): IRF6 (ENSG00000117595), IRF1 (ENSG00000125347), IRF3 (ENSG00000126456), IRF5 (ENSG00000128604), IRF4 (ENSG00000137265), IRF8 (ENSG00000140968), IRF2 (ENSG00000168310), IRF7 (ENSG00000185507)

Protein

Protein identifiers

Interferon regulatory factor 9 — Q00978 (reviewed: Q00978)

Alternative names: IFN-alpha-responsive transcription factor subunit, ISGF3 p48 subunit, Interferon-stimulated gene factor 3 gamma, Transcriptional regulator ISGF3 subunit gamma

All UniProt accessions (25): A0A8V8TMJ8, A0A8V8TMK5, A0A8V8TMN7, A0A8V8TMP0, A0A8V8TMP1, A0A8V8TMP6, A0A8V8TMQ7, A0A8V8TMU4, A0A8V8TMV6, A0A8V8TN13, A0A8V8TN47, A0A8V8TNB4, A0A8V8TP30, A0A8V8TP35, A0A8V8TP43, A0A8V8TP83, A0A8V8TPD7, A0A8V8TPF1, A0A8V8TPF5, A0A8V8TPL3, Q00978, H0YMB0, H0YNM9, H0YNP4, H7BXP4

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that plays an essential role in anti-viral immunity. It mediates signaling by type I IFNs (IFN-alpha and IFN-beta). Following type I IFN binding to cell surface receptors, Jak kinases (TYK2 and JAK1) are activated, leading to tyrosine phosphorylation of STAT1 and STAT2. IRF9/ISGF3G associates with the phosphorylated STAT1:STAT2 dimer to form a complex termed ISGF3 transcription factor, that enters the nucleus. ISGF3 binds to the IFN stimulated response element (ISRE) to activate the transcription of interferon stimulated genes, which drive the cell in an antiviral state.

Subunit / interactions. Interacts with STAT2 in the cytoplasm. Forms the interferon-stimulated gene factor 3 complex (ISGF3) with the heterodimer STAT1:STAT2; upon stimulation. (Microbial infection) Interacts with measles virus V protein; this interaction prevents the binding of IRF9 to STAT2 and thereby the type I interferon signaling pathway.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. (Microbial infection) Ubiquitinated by Herpes simplex virus 2 E3 ubiquitin ligase ICP22.

Disease relevance. Immunodeficiency 65 (IMD65) [MIM:618648] An autosomal recessive immunologic disorder characterized by recurrent viral infections from early infancy. Clinical consequences are pneumonia, bronchiectasis, and septic shock. Affected individuals have lymphopenia or hypogammaglobulinemia, particularly during infection, and impaired cellular type I interferon response. Patients may have adverse response to vaccination with live attenuated vaccines. The disease is caused by variants affecting the gene represented in this entry.

Induction. By IFN-alpha and IFNB1/IFN-beta.

Similarity. Belongs to the IRF family.

RefSeq proteins (4): NP_001372329, NP_001372330, NP_001372331, NP_006075* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001346	Interferon_reg_fact_DNA-bd_dom	Domain
IPR008984	SMAD_FHA_dom_sf	Homologous_superfamily
IPR017855	SMAD-like_dom_sf	Homologous_superfamily
IPR019471	Interferon_reg_factor-3	Domain
IPR019817	Interferon_reg_fac_CS	Conserved_site
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily

Pfam: PF00605, PF10401

UniProt features (9 total): region of interest 2, sequence variant 2, mutagenesis site 2, chain 1, DNA-binding region 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q00978-F1	75.82	0.43

Functional residue map

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

Post-translational modifications (1): 139

Mutagenesis-validated functional residues (2):

Position	Phenotype
81	loss of transcriptional activation in response to type i interferon stimulation. impaired anti-viral immunity.
292	decreased transcriptional activation in response to type i interferon stimulation. decreased anti-viral immunity.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-877300	Interferon gamma signaling
R-HSA-909733	Interferon alpha/beta signaling
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-168256	Immune System
R-HSA-913531	Interferon Signaling

MSigDB gene sets: 409 (showing top): WALLACE_PROSTATE_CANCER_RACE_UP, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, BECKER_TAMOXIFEN_RESISTANCE_UP, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, CAIRO_PML_TARGETS_BOUND_BY_MYC_DN, GGGTGGRR_PAX4_03, chr14q12, RODRIGUES_NTN1_TARGETS_DN, FERREIRA_EWINGS_SARCOMA_UNSTABLE_VS_STABLE_DN, YORDY_RECIPROCAL_REGULATION_BY_ETS1_AND_SP100_DN, ONKEN_UVEAL_MELANOMA_UP, UEDA_PERIFERAL_CLOCK, WANG_LMO4_TARGETS_DN

GO Biological Process (8): immune system process (GO:0002376), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), cell surface receptor signaling pathway (GO:0007166), positive regulation of transcription by RNA polymerase II (GO:0045944), defense response to virus (GO:0051607), regulation of DNA-templated transcription (GO:0006355), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (7): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription factor activity (GO:0003700), sequence-specific double-stranded DNA binding (GO:1990837), transcription cis-regulatory region binding (GO:0000976), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (6): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), ISGF3 complex (GO:0070721)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Interferon Signaling	2
Immune System	1
Cytokine Signaling in Immune system	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
regulation of DNA-templated transcription	3
DNA-templated transcription	3
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
biological_process	1
signal transduction	1
positive regulation of DNA-templated transcription	1
defense response	1
response to virus	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
nucleic acid binding	1
binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
RNA polymerase II transcription regulator complex	1

Protein interactions and networks

STRING

1712 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IRF9	STAT2	P52630	999
IRF9	STAT1	P42224	999
IRF9	JAK1	P23458	944
IRF9	IFNA13	P01562	916
IRF9	IFNB1	P01574	913
IRF9	TYK2	P29597	881
IRF9	IFNAR1	P17181	874
IRF9	STAT6	P42226	860
IRF9	MX1	P20591	835
IRF9	IFIT1	P09914	811
IRF9	STAT3	P40763	791
IRF9	IFIH1	Q9BYX4	781
IRF9	IFNAR2	P48551	773
IRF9	ISG15	P05161	770
IRF9	IFNA2	P01563	759

IntAct

40 interactions, top by confidence:

A	B	Type	Score
STAT1	STAT2	psi-mi:“MI:0914”(association)	0.930
STAT2	STAT1	psi-mi:“MI:0914”(association)	0.930
STAT2	IRF9	psi-mi:“MI:0915”(physical association)	0.880
IRF9	STAT2	psi-mi:“MI:0915”(physical association)	0.880
GYPA	TCAF2	psi-mi:“MI:0914”(association)	0.640
IFNAR2	IRF9	psi-mi:“MI:0914”(association)	0.620
IRF9	IFNAR2	psi-mi:“MI:0915”(physical association)	0.620
IFNAR2	IRF9	psi-mi:“MI:0915”(physical association)	0.620
STAT2	INPPL1	psi-mi:“MI:0914”(association)	0.530
IRF9	STAT1	psi-mi:“MI:0914”(association)	0.530
IRF9	IRF9	psi-mi:“MI:0915”(physical association)	0.400
NR2E3	IRF9	psi-mi:“MI:0915”(physical association)	0.370
TLX2	IRF9	psi-mi:“MI:0915”(physical association)	0.370
HOXC9	IRF9	psi-mi:“MI:0915”(physical association)	0.370
IRF1	IRF9	psi-mi:“MI:0915”(physical association)	0.370
POU2F1	IRF9	psi-mi:“MI:0915”(physical association)	0.370
IRF9	ARID3B	psi-mi:“MI:0915”(physical association)	0.370
IRF9	DACH2	psi-mi:“MI:0915”(physical association)	0.370
IRF9	VENTX	psi-mi:“MI:0915”(physical association)	0.370
IRF9	TLX3	psi-mi:“MI:0915”(physical association)	0.370
IRF9	DMRTC2	psi-mi:“MI:0915”(physical association)	0.370
IRF9	MYO1F	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (69): IRF9 (Affinity Capture-MS), STAT2 (Affinity Capture-MS), RAD18 (Affinity Capture-MS), ANKHD1-EIF4EBP3 (Affinity Capture-MS), UBE2R2 (Affinity Capture-MS), ARIH1 (Affinity Capture-MS), FBLN1 (Affinity Capture-MS), ANKHD1 (Affinity Capture-MS), ANKRD17 (Affinity Capture-MS), STAT1 (Two-hybrid), STAT2 (Two-hybrid), STAT1 (Reconstituted Complex), STAT2 (Reconstituted Complex), IRF9 (Affinity Capture-RNA), IRF9 (Affinity Capture-MS)

ESM2 similar proteins: A0A571BF63, A1L1K1, A2AVJ5, A2BID5, C9JE40, O02799, O70145, P0C6P5, P23611, P52630, P70671, P97433, P98150, Q00978, Q02556, Q0VA04, Q15306, Q1LXZ7, Q24151, Q2TAA8, Q3UIR3, Q4JF28, Q5E9R0, Q5GJ77, Q5RC07, Q5REG4, Q5T124, Q5XIZ9, Q61179, Q64287, Q6MZQ0, Q6ZUJ8, Q764M6, Q7QDU4, Q7Z3E5, Q80V91, Q8C3J5, Q8CDJ8, Q8N957, Q8N9I9

Diamond homologs: A0FIN4, O14896, P10914, P14316, P15314, P23570, P23611, P23906, P56477, P70671, P97431, Q00978, Q02556, Q08DD6, Q13568, Q14653, Q15306, Q3SZP0, Q4JF28, Q58DJ0, Q61179, Q64287, Q764M6, Q8R4E0, Q90643, Q90871, Q90876, Q98925, Q92985, F5HF68, P70434

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
IRF9	“up-regulates activity”	IFNAR2	binding
CREBBP	“up-regulates activity”	IRF9	acetylation
IRF9	“up-regulates activity”	STAT2	binding
IRF9	“form complex”	“ISGF3 complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 27 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
Interferon alpha/beta signaling	5	63.4×	8e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	141
Likely benign	107
Benign	7

Top pathogenic / likely-pathogenic (0)

SpliceAI

951 predictions. Top by Δscore:

Variant	Effect	Δscore
14:24162142:AGGAT:A	acceptor_gain	1.0000
14:24162143:GGATG:G	acceptor_gain	1.0000
14:24162961:CCTAG:C	acceptor_loss	1.0000
14:24162962:CTA:C	acceptor_loss	1.0000
14:24162963:TAGG:T	acceptor_loss	1.0000
14:24162964:A:AG	acceptor_gain	1.0000
14:24162964:A:AT	acceptor_loss	1.0000
14:24162964:AG:A	acceptor_gain	1.0000
14:24162965:G:GA	acceptor_loss	1.0000
14:24162965:G:GC	acceptor_loss	1.0000
14:24162965:G:GG	acceptor_gain	1.0000
14:24162965:GG:G	acceptor_gain	1.0000
14:24162965:GGC:G	acceptor_gain	1.0000
14:24162965:GGCC:G	acceptor_gain	1.0000
14:24162965:GGCCT:G	acceptor_gain	1.0000
14:24163146:TCTG:T	donor_gain	1.0000
14:24163148:TG:T	donor_gain	1.0000
14:24163148:TGGT:T	donor_loss	1.0000
14:24163149:GG:G	donor_gain	1.0000
14:24163149:GGTG:G	donor_loss	1.0000
14:24163150:G:C	donor_loss	1.0000
14:24163150:G:GG	donor_gain	1.0000
14:24163151:T:A	donor_loss	1.0000
14:24163365:A:AG	acceptor_gain	1.0000
14:24163366:A:G	acceptor_gain	1.0000
14:24163367:C:G	acceptor_gain	1.0000
14:24163368:A:AG	acceptor_gain	1.0000
14:24163369:A:G	acceptor_gain	1.0000
14:24163373:CACA:C	acceptor_loss	1.0000
14:24163374:A:AG	acceptor_gain	1.0000

AlphaMissense

2571 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:24162257:T:C	F38S	0.999
14:24162268:T:A	W42R	0.999
14:24162268:T:C	W42R	0.999
14:24162270:G:C	W42C	0.999
14:24162270:G:T	W42C	0.999
14:24162969:T:A	W62R	0.999
14:24162969:T:C	W62R	0.999
14:24163028:G:C	K81N	0.999
14:24163028:G:T	K81N	0.999
14:24162189:G:C	W15C	0.998
14:24162189:G:T	W15C	0.998
14:24162971:G:C	W62C	0.998
14:24162971:G:T	W62C	0.998
14:24163026:A:C	K81Q	0.998
14:24163026:A:G	K81E	0.998
14:24163027:A:C	K81T	0.998
14:24163066:T:C	F94S	0.998
14:24163119:T:G	Y112D	0.998
14:24162187:T:A	W15R	0.997
14:24162187:T:C	W15R	0.997
14:24162260:G:C	R39P	0.997
14:24162276:T:A	H44Q	0.997
14:24162276:T:G	H44Q	0.997
14:24163038:C:A	R85S	0.997
14:24163048:T:C	L88P	0.997
14:24163115:G:C	K110N	0.997
14:24163115:G:T	K110N	0.997
14:24162232:T:A	W30R	0.996
14:24162232:T:C	W30R	0.996
14:24162234:G:C	W30C	0.996

dbSNP variants (sampled 300 via entrez): RS1000222186 (14:24163934 C>G,T), RS1000825808 (14:24165505 G>A), RS1003117888 (14:24161222 TGGA>T), RS1003456816 (14:24159589 A>G), RS1003486635 (14:24159290 T>C), RS1003847390 (14:24159934 T>C), RS1003957095 (14:24165641 T>TA), RS1005025054 (14:24166533 A>G), RS1005808454 (14:24161740 C>G,T), RS1005925005 (14:24161538 G>A), RS1006392525 (14:24161817 A>G), RS1006988097 (14:24161343 GATCAGCCAAGGATGGGA>G), RS1007623119 (14:24162577 G>A), RS1007769926 (14:24162002 T>C), RS1008278337 (14:24165548 C>G)

Disease associations

OMIM: gene MIM:147574 | disease phenotypes: MIM:618648

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 65, susceptibility to viral infections	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
immunodeficiency 65, susceptibility to viral infections	Moderate	AR

Mondo (1): immunodeficiency 65, susceptibility to viral infections (MONDO:0032848)

Orphanet (0):

HPO phenotypes

6 total (6 of 6 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000230	Gingivitis
HP:0002110	Bronchiectasis
HP:0004429	Recurrent viral infections
HP:0010280	Stomatitis
HP:0031123	Recurrent gastroenteritis

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Resveratrol	decreases expression, increases expression, affects cotreatment	3
Estradiol	affects cotreatment, increases expression, decreases expression	3
Tetrachlorodibenzodioxin	increases expression	3
Valproic Acid	affects expression, decreases expression	3
Acetaminophen	decreases expression, increases expression	2
Benzo(a)pyrene	increases expression	2
Fluorouracil	increases expression	2
Lipopolysaccharides	increases expression, affects response to substance	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Plant Extracts	affects cotreatment, increases expression	2
Poly I-C	decreases reaction, increases expression	2
Silicon Dioxide	decreases expression, increases expression	2
Tretinoin	increases expression	2
Cyclosporine	increases expression	2
bisphenol F	affects cotreatment, increases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
geraniol	increases expression	1
salinomycin	decreases expression	1
benzo(e)pyrene	decreases methylation	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	decreases expression	1
tamibarotene	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1

Cellosaurus cell lines

11 cell lines: 6 cancer cell line, 3 embryonic stem cell, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A3H4	SEES3-1V human IRF9, clone1	Embryonic stem cell	Male
CVCL_A3H5	SEES3-1V human IRF9, clone2	Embryonic stem cell	Male
CVCL_A3H6	SEES3-1V human IRF9, clone3	Embryonic stem cell	Male
CVCL_AW29	K562 eGFP-IRF9	Cancer cell line	Female
CVCL_B1UR	Abcam HeLa IRF9 KO	Cancer cell line	Female
CVCL_B2NM	Abcam A-549 IRF9 KO	Cancer cell line	Male
CVCL_D7SI	Ubigene A-549 IRF9 KO	Cancer cell line	Male
CVCL_D8NE	Ubigene HCT 116 IRF9 KO	Cancer cell line	Male
CVCL_E0FC	Ubigene HeLa IRF9 KO	Cancer cell line	Female
CVCL_E8DB	HEK-Blue IFN-alpha/beta v2	Transformed cell line	Female

Clinical trials (associated diseases)

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