IRGM

Summary

IRGM (immunity related GTPase M, HGNC:29597) is a protein-coding gene on chromosome 5q33.1, encoding Immunity-related GTPase family M protein (A1A4Y4). Immunity-related GTPase that plays important roles in innate immunity and inflammatory response.

This gene encodes a member of the p47 immunity-related GTPase family. The encoded protein may play a role in the innate immune response by regulating autophagy formation in response to intracellular pathogens. Polymorphisms that affect the normal expression of this gene are associated with a susceptibility to Crohn’s disease and tuberculosis. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 345611 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 115 total
• Phenotypes (HPO): 1
• Druggable target: yes
• MANE Select transcript: NM_001145805

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29597
Approved symbol	IRGM
Name	immunity related GTPase M
Location	5q33.1
Locus type	gene with protein product
Status	Approved
Aliases	LRG47, LRG-47, IFI1
Ensembl gene	ENSG00000237693
Ensembl biotype	protein_coding
OMIM	608212
Entrez	345611

Gene structure

Transcript identifiers

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

ENST00000520549, ENST00000522154, ENST00000609660, ENST00000951736

RefSeq mRNA: 1 — MANE Select: NM_001145805 NM_001145805

CCDS: CCDS47313

Canonical transcript exons

ENST00000522154 — 2 exons

Exon	Start	End
ENSE00002135949	150846521	150847220
ENSE00002136880	150847709	150848702

Expression profiles

Bgee: expression breadth ubiquitous, 143 present calls, max score 84.04.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0154 / max 4.6635, expressed in 6 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
203744	0.0154	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.04	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.39	gold quality
granulocyte	CL:0000094	61.90	gold quality
bone marrow cell	CL:0002092	57.63	silver quality
calcaneal tendon	UBERON:0003701	56.21	gold quality
vermiform appendix	UBERON:0001154	56.18	gold quality
lymph node	UBERON:0000029	55.27	gold quality
stromal cell of endometrium	CL:0002255	54.70	gold quality
small intestine Peyer’s patch	UBERON:0003454	53.47	gold quality
blood	UBERON:0000178	52.73	gold quality
caecum	UBERON:0001153	52.63	gold quality
smooth muscle tissue	UBERON:0001135	52.08	gold quality
metanephros cortex	UBERON:0010533	51.60	gold quality
small intestine	UBERON:0002108	51.48	gold quality
gall bladder	UBERON:0002110	51.33	gold quality
spleen	UBERON:0002106	51.17	gold quality
omental fat pad	UBERON:0010414	50.59	gold quality
peritoneum	UBERON:0002358	50.56	gold quality
tendon	UBERON:0000043	50.11	gold quality
mucosa of stomach	UBERON:0001199	50.04	gold quality
adipose tissue of abdominal region	UBERON:0007808	50.04	gold quality
bone marrow	UBERON:0002371	49.88	gold quality
right ovary	UBERON:0002118	49.35	gold quality
rectum	UBERON:0001052	49.25	gold quality
body of stomach	UBERON:0001161	49.15	gold quality
lower esophagus mucosa	UBERON:0035834	48.50	gold quality
metanephros	UBERON:0000081	48.21	gold quality
stomach	UBERON:0000945	47.93	gold quality
subcutaneous adipose tissue	UBERON:0002190	47.45	gold quality
adipose tissue	UBERON:0001013	46.81	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.25

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 40)

• identified a function for IRGM in the control of intracellular pathogens and report that IRGM plays a role in autophagy and in the reduction of intracellular Mycobacterium var. bovis BCG load (PMID:16888103)
• Genetic evidence implicates IRGM defects in the early immune response in individuals with Crohn’s disease. (PMID:17554261)
• IRGM is significantly associated with Crohn disease. (PMID:17921695)
• This study has confirmed NCF4 and IRGM are risk factors for ileal Crohn’s disease in New Zealand Caucasians. (PMID:18580884)
• The frequency of IRGM polymorphism rs10065172 was higher in cases but differences with controls were not statistically significant in children with Crohn disease (PMID:18985712)
• IRGM is a susceptibility locus for CD, either adult- or early-onset; furthermore, we have also shown its influence on specific clinical features (fistulizing disease). (PMID:19098858)
• a genetic risk locus for Crohn’s disease, a common form of inflammatory bowel disease (PMID:19120485)
• These results suggest that the CD association at IRGM arises from an alteration in IRGM regulation that affects the efficacy of autophagy and identify a common deletion polymorphism as a likely causal variant (PMID:19165925)
• genetic associations for CD with IL23R, ATG16L1, IRGM, NKX2-3, 1q24, 10q21, 5p13, and PTPN2 and report evidence for associations with HERC2 and CCNY. (PMID:19174780)
• The restoration of the IRGM gene coincided with the insertion of an endogenous retrovirus. (PMID:19266026)
• the ATG16L1 rs2241880 and IRGM rs13361189 and rs4958847 polymorphisms are important markers for Crohn’s disease susceptibility and indicate that these variants are also associated with ulcerative colitis. (PMID:19491842)
• no evidence of association with celiac disease has been reported for the Crohn’s disease susceptibility polymorphisms studied in the NKX2-3, ATG16L1, and IRGM genes. (PMID:19683022)
• Results suggest a role for IRGM and autophagy in protection of humans against natural infection with M. tuberculosis Euro-American clades. (PMID:19750224)
• Small insertion/deletion polymorphisms in the promoter and 5’ untranslated region of IRGM are, together with the copy number variation, strongly associated with Crohn’s disease. (PMID:20106866)
• The association of the ATG16L1 variant and IRGM variants with Crohn’s disease was confirmed. No evidence for gene-gene interaction between ATG16L1 and IRGM and granuloma formation was found. (PMID:20395867)
• In 1.7 kb IRGM promoter region, only -1208A/G polymorphism is associated with susceptibility to TB (PMID:20547146)
• the unusual evolutionary history of the IRGM locus and the important role of the IRGM gene in autophagy and Crohn’s disease in response to pathogenesis. (PMID:20737271)
• Data suggest that NKX2-3 and IRGM are susceptibility loci for inflammatory bowel disease in Eastern European patients. (PMID:21049557)
• Data show that an additive gene-gene interaction involving TLR4, PSMG1, TNFRSF6B and IRGM was identified with CD. (PMID:21079743)
• IRGM demonstrated differential affinity for the mitochondrial lipid cardiolipin, translocated to mitochondria, affected mitochondrial fission and induced autophagy. (PMID:21102437)
• this Crohn’s Disease-related IRGM1 polymorphic allele is also associated with human susceptibility to tuberculosis disease among African Americans (PMID:21283700)
• a critical “menage a trois” in risk susceptibility to Crohn disease combining IRGM allele, miRNA and xenophagy (PMID:21508684)
• Irgm3 relieves the ER stress response via a PI3K/Akt dependent mechanism, which contributes to host defence against coxsackievirus B3 infection. (PMID:21981022)
• IFN-gamma enhances Con A-induced autophagic flux and causes an IRGM1-dependent lysosome-mediated necrotic cell death in hepatocytes (PMID:22163006)
• Our work reveals an unexpected role of IRGM in virus-induced autophagy (PMID:22174682)
• Single-nucleotide polymorphism rs4958847 in the IRGM gene correlated very significantly with frequency of surgery in patients with ileocolonic Crohn’s disease. (PMID:22228152)
• Variants in the genes ATG16L1 and IRGM affect autophagy and are associated with the development of Crohn’s disease (PMID:22370477)
• IRGM single nucleotide polymorphisms are associated with Crohn’s disease. (PMID:22508677)
• In a Portuguese population, SNPs at three autophagy-related genes, ATG16L1, IRGM, and ITLN1, contribute to predict Crohn’s ileal or ileocolonic disease, involvement of the upper digestive tract, and response to treatment. (PMID:22573572)
• IRGM rs4958847 polymorphism influences susceptibility to gastric cancer, mainly for the intestinal type. (PMID:22713085)
• IRGM polymorphisms are associated with decreased susceptibility to pulmonary tuberculosis. (PMID:23049477)
• IRGM is a susceptibility gene for Crohn’s disease in the German population. (PMID:23365659)
• These results indicated that autophagy gene-IRGM polymorphisms appear to confer susceptibility to CD but not UC, especially in Europeans. (PMID:24232856)
• IRGM gene polymorphism is associated with the increased risk of leprosy by affecting inflammatory cytokines. (PMID:24264476)
• IRGM expression is upregulated in monocytes and monocyte-derived macrophages by Mycobacterium leprae (PMID:24469081)
• This is the first study to identify a significant association between the IRGM single-nucleotide polymorphism (SNP) rs10065172 and susceptibility to active tuberculosis disease in an Asian population. (PMID:24595493)
• the IRGM(+313), an autophagy-related polymorphic locus, influences outcome in severely septic patients, with the possible involvement of autophagy in sepsis exacerbation (PMID:24626347)
• the presence of the IRGM1 rs13361189 variant allele was associated with a lower use of immunosuppressant therapy, high-lighting a possible role in the development of a milder phenotype. (PMID:24656308)
• Despite moderate effects on the modulation of proinflammatory cytokine production, genetic variation in the autophagy genes ATG16L1 and IRGM has a minor impact on the susceptibility to both mucosal and systemic Candida infections. (PMID:24713404)
• a potential role of IRGM in the development of glioma probably by affecting IFN-gamma and IL-4. (PMID:24859836)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	irgf3	ENSDARG00000062820
danio_rerio	si:ch73-171o20.1	ENSDARG00000062828
danio_rerio	irgf1	ENSDARG00000070774
danio_rerio	irgf2	ENSDARG00000092249
mus_musculus	Irgm1	ENSMUSG00000046879
mus_musculus	Irgm2	ENSMUSG00000069874
mus_musculus	Igtp	ENSMUSG00000078853
rattus_norvegicus	Igtp	ENSRNOG00000027008
rattus_norvegicus	Irgm	ENSRNOG00000031138
rattus_norvegicus		ENSRNOG00000073574

Paralogs (1): IRGC (ENSG00000124449)

Protein

Protein identifiers

Immunity-related GTPase family M protein — A1A4Y4 (reviewed: A1A4Y4)

Alternative names: Immunity-related GTPase family M protein 1, Interferon-inducible protein 1, LPS-stimulated RAW 264.7 macrophage protein 47 homolog

All UniProt accessions (2): A1A4Y4, A0A9H4B933

UniProt curated annotations — full annotation on UniProt →

Function. Immunity-related GTPase that plays important roles in innate immunity and inflammatory response. Acts as a dynamin-like protein that binds to intracellular membranes and promotes remodeling and trafficking of those membranes. Required for clearance of acute protozoan and bacterial infections by interacting with autophagy and lysosome regulatory proteins, thereby promoting the fusion of phagosomes with lysosomes for efficient degradation of cargo including microbes. Regulates selective autophagy, including xenophagy and mitophagy, both directly and indirectly. Directly regulates autophagy by acting as a molecular adapter that promotes the coassembly of the core autophagy machinery to mediate antimicrobial defense: IRGM (1) activates AMPK, which in turn phosphorylates ULK1 and BECN1 to induce autophagy, (2) promotes the coassembly of ULK1 and BECN1, enhancing BECN1-interacting partners and (3) influences the composition of the BECN1 complex, by competing with the negative regulators BCL2 and RUBCN, to trigger autophagy. Also activates autophagy by promoting recruitment of STX17 to autophagosomes. In collaboration with ATG8 proteins, regulate lysosomal biogenesis, a fundamental process for any autophagic pathway, by promoting TFEB dephosphorylation. Also modulates autophagy by assisting with autophagosome formation and preventing lysosomal deacidification. While activating autophagy, acts as a key negative regulator of the inflammatory and interferon responses both by (1) promoting mitophagy and (2) mediating autophagy-dependent degradation of effectors of the inflammatory response. Promotes degradation of damaged and IFNG/IFN-gamma-stressed mitochondria via mitophagy, preventing cytosolic release of ligands that activate inflammation. Acts as a suppressor of inflammation by promoting recruitment of inflammation effectors, such as CGAS, RIGI/RIG-I and NLRP3, to autophagosome membranes, leading to their SQSTM1/p62-dependent autophagic degradation. Also directly inhibits assembly of the NLRP3 inflammasome by preventing the association between NLRP3 and PYCARD. Acts as a negative regulator of antiviral innate immune response by suppressing the RIPK2-dependent pro-inflammatory response: mediates recruitment of RIPosomes, composed of RIPK2 and NOD1 or NOD2, to autophagosome membranes, promoting their SQSTM1/p62-dependent autophagic degradation. Acts as a positive regulator of mitophagy in response to intracellular mycobacteria infection: specifically binds cardiolipin, leading to its translocation to mitochondria, where it promotes affected mitochondrial fission and mitophagy. (Microbial infection) Following infection by hepatitis C virus (HCV), promotes HCV-triggered membrane remodeling, leading to autophagy and Golgi fragmentation, a step required for HCV replication.

Subunit / interactions. Interacts with ULK1; promoting the coassembly of ULK1 and BECN1. Interacts with BECN1; enhancing BECN1-interacting partners and influencing the composition of the BECN1 complex. Interacts with ATG16L1. Interacts with NOD2; promoting IRGM ‘Lys-63’-linked polyubiquitination, which is required for interactions with the core autophagy factors. Interacts with STX17; promoting STX17 recruitment to autophagosomes. Interacts with ATG8 proteins (GABARAP, GABARAPL1, GABARAPL2, MAP1LC3A, MAP1LC3B and MAP1LC3C); promoting STX17 recruitment to autophagosomes. Interacts with TFEB; promoting association between TFEB and PPP3CB and TFEB dephosphorylation. Interacts with PPP3CB; promoting association between TFEB and PPP3CB and TFEB dephosphorylation. Interacts with NLRP3; preventing NLRP3 inflammasome assembly and promoting SQSTM1/p62-dependent autophagic degradation of NLRP3. Interacts with CGAS; promoting SQSTM1/p62-dependent autophagic degradation of CGAS. Interacts with RIGI/RIG-I; promoting SQSTM1/p62-dependent autophagic degradation of RIGI/RIG-I. Interacts with NOD1; promoting SQSTM1/p62-dependent autophagic degradation of RIGI/RIG-I. Interacts with NOD2; promoting SQSTM1/p62-dependent autophagic degradation of RIGI/RIG-I. Interacts with RIPK2; promoting SQSTM1/p62-dependent autophagic degradation of RIGI/RIG-I.

Subcellular location. Golgi apparatus membrane. Cell membrane. Cytoplasmic vesicle. Phagosome membrane. Autophagosome membrane. Lysosome membrane. Late endosome membrane. Mitochondrion membrane. Cell projection. Phagocytic cup Mitochondrion.

Tissue specificity. Widely expressed (at protein level). Expressed in several tissues including colon, small bowel and peripheral blood leukocytes.

Post-translational modifications. Ubiquitinated via ‘Lys-63’-linked polyubiquitination in a NOD2-dependent process. ‘Lys-63’-linked polyubiquitination is required for interactions with the core autophagy factors.

Disease relevance. Inflammatory bowel disease 19 (IBD19) [MIM:612278] A chronic, relapsing inflammation of the gastrointestinal tract with a complex etiology. It is subdivided into Crohn disease and ulcerative colitis phenotypes. Crohn disease may affect any part of the gastrointestinal tract from the mouth to the anus, but most frequently it involves the terminal ileum and colon. Bowel inflammation is transmural and discontinuous; it may contain granulomas or be associated with intestinal or perianal fistulas. In contrast, in ulcerative colitis, the inflammation is continuous and limited to rectal and colonic mucosal layers; fistulas and granulomas are not observed. Both diseases include extraintestinal inflammation of the skin, eyes, or joints. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Domain organisation. The G5 motif of the IRG-type G domain is missing because the IRGM protein is truncated in anthropoids.

Induction. Not up-regulated by IFNG/IFN-gamma.

Polymorphism. Genetic variations in the IRGM promoter determine Mycobacterium tuberculosis susceptibility [MIM:607948]. People that are homozygote for -261C-T (rs9637876) variant, which is located within an Alu sequence in the promoter region, are associated with protection from M.tuberculosis. In contrast, -261T-T allele is significantly associated with protection from pulmonary tuberculosis caused by M.tuberculosis, but not by M.africanum, a strain restricted to West Africa, or M.bovis.

Miscellaneous. There is a huge difference in terms of sequence and regulation of expression compared to the mouse ortholog and hence, the function might be slightly different.

Similarity. Belongs to the TRAFAC class dynamin-like GTPase superfamily. IRG family.

Isoforms (4)

UniProt ID	Names	Canonical?
A1A4Y4-1	IRGMa	yes
A1A4Y4-2	IRGMb
A1A4Y4-3	IRGMc, IRGMe
A1A4Y4-4	IRGMd

RefSeq proteins (1): NP_001139277* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007743	Immunity-related_GTPase-like	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR030385	G_IRG_dom	Domain
IPR051515	IRG	Family

Pfam: PF05049

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (11 total): binding site 3, splice variant 3, sequence variant 2, chain 1, domain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A1A4Y4-F1	84.60	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.

Ligand- & substrate-binding residues (3): 41–48; 66–70; 147–149

Mutagenesis-validated functional residues (1):

Position	Phenotype
47	abolished gtpase activity, preventing interaction with stx17 and/or nlrp3.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 417 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_CELLULAR_RESPONSE_TO_VIRUS, GOBP_POSITIVE_REGULATION_OF_MITOCHONDRIAL_FISSION, GOBP_POSITIVE_REGULATION_OF_MACROPHAGE_ACTIVATION, GOBP_VACUOLE_ORGANIZATION, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_DEFENSE_RESPONSE_TO_VIRUS, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_LIPOPROTEIN_METABOLIC_PROCESS, GOCC_VACUOLAR_MEMBRANE

GO Biological Process (46): autophagosome assembly (GO:0000045), positive regulation of protein phosphorylation (GO:0001934), inflammatory response (GO:0006954), positive regulation of autophagy (GO:0010508), positive regulation of peptidyl-threonine phosphorylation (GO:0010800), protein destabilization (GO:0031648), negative regulation of type I interferon production (GO:0032480), negative regulation of type II interferon production (GO:0032689), positive regulation of peptidyl-serine phosphorylation (GO:0033138), cellular response to interferon-beta (GO:0035458), defense response to bacterium (GO:0042742), positive regulation of macrophage activation (GO:0043032), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), regulation of protein-containing complex assembly (GO:0043254), innate immune response (GO:0045087), negative regulation of defense response to virus (GO:0050687), negative regulation of inflammatory response (GO:0050728), protein stabilization (GO:0050821), defense response to Gram-negative bacterium (GO:0050829), positive regulation of type II interferon-mediated signaling pathway (GO:0060335), regulation of protein complex stability (GO:0061635), protein lipidation involved in autophagosome assembly (GO:0061739), CAMKK-AMPK signaling cascade (GO:0061762), protein-containing complex assembly (GO:0065003), nucleotide-binding oligomerization domain containing 2 signaling pathway (GO:0070431), protein targeting to vacuole involved in autophagy (GO:0071211), cellular response to lipopolysaccharide (GO:0071222), positive regulation of protein serine/threonine kinase activity (GO:0071902), positive regulation of mitochondrial fission (GO:0090141), autophagosome maturation (GO:0097352), cellular response to virus (GO:0098586), negative regulation of cGAS/STING signaling pathway (GO:0160049), negative regulation of NLRP3 inflammasome complex assembly (GO:1900226), positive regulation of autophagosome maturation (GO:1901098), positive regulation of mitophagy (GO:1901526), positive regulation of xenophagy (GO:1904417), positive regulation of lysosome organization (GO:1905673), immune system process (GO:0002376), autophagy (GO:0006914), lysosome organization (GO:0007040)

GO Molecular Function (12): GTPase activity (GO:0003924), G protein activity (GO:0003925), GTP binding (GO:0005525), protein kinase binding (GO:0019901), protein-macromolecule adaptor activity (GO:0030674), protein serine/threonine kinase activator activity (GO:0043539), CARD domain binding (GO:0050700), BH3 domain binding (GO:0051434), cardiolipin binding (GO:1901612), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (17): Golgi membrane (GO:0000139), autophagosome membrane (GO:0000421), phagocytic cup (GO:0001891), mitochondrion (GO:0005739), lysosomal membrane (GO:0005765), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), cytosol (GO:0005829), phagocytic vesicle membrane (GO:0030670), late endosome membrane (GO:0031902), mitochondrial membrane (GO:0031966), lysosome (GO:0005764), endosome (GO:0005768), plasma membrane (GO:0005886), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	4
defense response	2
positive regulation of protein phosphorylation	2
regulation of protein stability	2
negative regulation of cytokine production	2
negative regulation of defense response	2
negative regulation of response to external stimulus	2
intracellular membrane-bounded organelle	2
organelle membrane	2
endomembrane system	2
Atg12 activating enzyme activity	1
protein-phosphatidylethanolamide deconjugating activity	1
Atg12 conjugating enzyme activity	1
Atg12 ligase activity	1
organelle assembly	1
Atg1/ULK1 kinase complex assembly	1
autophagosome organization	1
regulation of protein phosphorylation	1
protein phosphorylation	1
positive regulation of protein modification process	1
positive regulation of phosphorylation	1
autophagy	1
positive regulation of catabolic process	1
regulation of autophagy	1
regulation of peptidyl-threonine phosphorylation	1
peptidyl-threonine phosphorylation	1
regulation of type I interferon production	1
type I interferon production	1
type II interferon production	1
regulation of type II interferon production	1
peptidyl-serine phosphorylation	1
regulation of peptidyl-serine phosphorylation	1
response to interferon-beta	1
cellular response to cytokine stimulus	1
response to bacterium	1
positive regulation of leukocyte activation	1
macrophage activation	1
regulation of macrophage activation	1
canonical NF-kappaB signal transduction	1

Protein interactions and networks

STRING

1739 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IRGM	ATG5	Q9H1Y0	988
IRGM	ATG10	Q9H0Y0	987
IRGM	ATG16L1	Q676U5	960
IRGM	NOD2	Q9HC29	861
IRGM	BECN1	Q14457	838
IRGM	ZNF300	Q96RE9	826
IRGM	SH3GLB1	Q9Y371	803
IRGM	SNAPIN	O95295	734
IRGM	TSPAN8	P19075	707
IRGM	GABARAPL2	P60520	687
IRGM	F5GZY7	F5GZY7	687
IRGM	SQSTM1	Q13501	686
IRGM	RIGI	O95786	685
IRGM	TLR4	O00206	676
IRGM	SLC11A1	P49279	675

IntAct

7 interactions, top by confidence:

A	B	Type	Score
IRGM	OPTN	psi-mi:“MI:0915”(physical association)	0.560
IRGM	CFL1	psi-mi:“MI:0915”(physical association)	0.400
IRGM	HOXD13	psi-mi:“MI:0914”(association)	0.350
IRGM	TBC1D4	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (57): ULK1 (Affinity Capture-Western), AMBRA1 (Affinity Capture-Western), BECN1 (Affinity Capture-Western), IRGM (Affinity Capture-Western), ATG14 (Affinity Capture-Western), ATG16L1 (Affinity Capture-Western), IRGM (Affinity Capture-Western), NOD2 (Affinity Capture-Western), IRGM (Affinity Capture-Western), IRGM (Reconstituted Complex), IRGM (Affinity Capture-Western), NOD1 (Affinity Capture-Western), IRGM (Affinity Capture-Western), TLR3 (Affinity Capture-Western), IRGM (Affinity Capture-Western)

ESM2 similar proteins: A0A140LIF8, A0A2P1BRP3, A0A386CAB9, A0JN92, A1A4Y4, O14791, P27473, P59045, P86448, P86449, Q0GUM3, Q13075, Q3B7D9, Q3T9E4, Q3TL54, Q53G44, Q5NCI0, Q5RFJ8, Q60766, Q62293, Q66X01, Q66X03, Q66X05, Q66X22, Q6AYC2, Q6ZSC3, Q7Z745, Q84WJ0, Q86W28, Q8BV66, Q8BVM9, Q8C6J9, Q8CBA2, Q8CCN1, Q8TCB0, Q8TCY9, Q8TD90, Q90597, Q99388, Q99J64

Diamond homologs: A0A140LIF8, A1A4Y4, Q0GUM3, Q32KW9, Q3T9E4, Q60766, Q62293, Q6AYC2, Q6AYF9, Q6NXR0, Q9DCE9, Q9QZ85, Q8C262, Q8VIM9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	99
Likely benign	9
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

499 predictions. Top by Δscore:

Variant	Effect	Δscore
5:150898056:A:AC	donor_gain	1.0000
5:150898057:C:CC	donor_gain	1.0000
5:150898059:T:TA	donor_gain	1.0000
5:150898115:C:CA	donor_gain	1.0000
5:150898181:TACC:T	acceptor_gain	1.0000
5:150898183:CC:C	acceptor_gain	1.0000
5:150898184:CCTAT:C	acceptor_gain	1.0000
5:150898185:C:CA	acceptor_loss	1.0000
5:150898185:C:CC	acceptor_gain	1.0000
5:150896970:CTGT:C	acceptor_gain	0.9900
5:150898072:ATCTG:A	donor_gain	0.9900
5:150898076:G:A	donor_gain	0.9900
5:150898088:T:C	donor_gain	0.9900
5:150898182:ACC:A	acceptor_gain	0.9900
5:150898183:CCC:C	acceptor_gain	0.9900
5:150898185:C:T	acceptor_gain	0.9900
5:150898188:T:C	acceptor_gain	0.9900
5:150898188:T:TC	acceptor_gain	0.9900
5:150898422:CCTTA:C	donor_loss	0.9900
5:150898423:CTTAC:C	donor_loss	0.9900
5:150898424:TTA:T	donor_loss	0.9900
5:150898425:TA:T	donor_loss	0.9900
5:150898426:A:AC	donor_gain	0.9900
5:150898426:ACCC:A	donor_loss	0.9900
5:150898427:C:CC	donor_gain	0.9900
5:150896974:C:CC	acceptor_gain	0.9800
5:150898180:ATACC:A	acceptor_gain	0.9800
5:150898193:C:CT	acceptor_gain	0.9800
5:150898426:AC:A	donor_gain	0.9800
5:150898427:CC:C	donor_gain	0.9800

AlphaMissense

1196 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:150848544:T:C	F141L	0.805
5:150848546:C:A	F141L	0.805
5:150848546:C:G	F141L	0.805
5:150848490:T:C	F123L	0.791
5:150848492:C:A	F123L	0.791
5:150848492:C:G	F123L	0.791
5:150848370:T:C	F83L	0.712
5:150848372:T:A	F83L	0.712
5:150848372:T:G	F83L	0.712
5:150848451:T:C	F110L	0.673
5:150848453:C:A	F110L	0.673
5:150848453:C:G	F110L	0.673
5:150848466:T:C	F115L	0.673
5:150848468:C:A	F115L	0.673
5:150848468:C:G	F115L	0.673
5:150848268:T:C	F49L	0.663
5:150848270:C:A	F49L	0.663
5:150848270:C:G	F49L	0.663

dbSNP variants (sampled 300 via entrez): RS1000009084 (5:150900856 C>T), RS1000113 (5:150860514 C>T), RS1000143829 (5:150877665 G>C), RS1000183137 (5:150878523 A>G,T), RS1000226315 (5:150869217 T>C), RS1000241179 (5:150855051 A>G), RS1000287619 (5:150892967 T>C), RS1000387309 (5:150848177 G>A), RS1000442989 (5:150871060 T>G), RS1000458657 (5:150875140 G>A), RS1000515839 (5:150881651 A>G), RS1000569416 (5:150847541 C>G,T), RS1000595499 (5:150893954 T>G), RS1000662136 (5:150854645 T>G), RS1000749277 (5:150887603 A>G,T)

Disease associations

OMIM: gene MIM:608212 | disease phenotypes: MIM:612278

GenCC curated gene-disease

Mondo (1): inflammatory bowel disease 19 (MONDO:0012845)

Orphanet (0):

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0002037	Inflammation of the large intestine

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST000039_5	Crohn’s disease	2.000000e-10
GCST000042_3	Crohn’s disease	3.000000e-07
GCST000207_14	Crohn’s disease	3.000000e-16
GCST000879_50	Crohn’s disease	8.000000e-19
GCST001725_71	Inflammatory bowel disease	3.000000e-37
GCST004131_47	Inflammatory bowel disease	3.000000e-15
GCST004132_24	Crohn’s disease	2.000000e-19
GCST005537_233	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	2.000000e-42
GCST005758_8	Dimensional psychopathology (Arousal)	5.000000e-07
GCST005855_1	Cholangiocarcinoma in primary sclerosing cholangitis	1.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009099	arousal domain measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567372	Inflammatory Bowel Disease 19 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5169093 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1000113	IRGM		0.00	0

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
propionaldehyde	increases expression	1
trichostatin A	affects expression	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
15-acetyldeoxynivalenol	increases expression	1
ginsenoside Re	decreases expression	1
abrine	increases expression	1
Glyphosate	increases expression	1
Benzo(a)pyrene	increases methylation	1
Cannabidiol	affects expression	1
Dimethyl Sulfoxide	affects expression	1
Thiram	increases expression	1
Valproic Acid	increases methylation	1
Cadmium Chloride	increases expression	1
Okadaic Acid	increases expression	1
Magnetite Nanoparticles	increases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5110771	Binding	Binding affinity to IRGM (unknown origin) by gene ontology analysis	SILAC-based chemoproteomics reveals a neoligan analogue as an anti-inflammatory agent targeting IRGM to ameliorate cytokine storm. — Eur J Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E1E2	Ubigene U-251 MG IRGM KO	Cancer cell line	Male

Clinical trials (associated diseases)

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