AIFM2

Summary

AIFM2 (AIF family member 2, ferroptosis suppressor, HGNC:21411) is a protein-coding gene on chromosome 10q22.1, encoding Ferroptosis suppressor protein 1 (Q9BRQ8). A NAD(P)H-dependent oxidoreductase that acts as a key inhibitor of ferroptosis.

This gene encodes a flavoprotein oxidoreductase that binds single stranded DNA and is thought to contribute to apoptosis in the presence of bacterial and viral DNA. The expression of this gene is also found to be induced by tumor suppressor protein p53 in colon cancer cells.

Source: NCBI Gene 84883 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 89 total
• Druggable target: yes
• MANE Select transcript: NM_032797

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21411
Approved symbol	AIFM2
Name	AIF family member 2, ferroptosis suppressor
Location	10q22.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ14497, PRG3, FSP1
Ensembl gene	ENSG00000042286
Ensembl biotype	protein_coding
OMIM	605159
Entrez	84883

Gene structure

Transcript identifiers

Ensembl transcripts: 56 — 55 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000307864, ENST00000373248, ENST00000482166, ENST00000613322, ENST00000856741, ENST00000856742, ENST00000856743, ENST00000856744, ENST00000856745, ENST00000856746, ENST00000856747, ENST00000856748, ENST00000856749, ENST00000856750, ENST00000856751, ENST00000856752, ENST00000856753, ENST00000856754, ENST00000856755, ENST00000856756, ENST00000856757, ENST00000856758, ENST00000856759, ENST00000856760, ENST00000856761, ENST00000856762, ENST00000856763, ENST00000856764, ENST00000856765, ENST00000856766, ENST00000924430, ENST00000924431, ENST00000924432, ENST00000959255, ENST00000959256, ENST00000959257, ENST00000959258, ENST00000959259, ENST00000959260, ENST00000959261, ENST00000959262, ENST00000959263, ENST00000959264, ENST00000959265, ENST00000959266, ENST00000959267, ENST00000959268, ENST00000959269, ENST00000959270, ENST00000959271, ENST00000959272, ENST00000959273, ENST00000959274, ENST00000959275, ENST00000959276, ENST00000959277

RefSeq mRNA: 2 — MANE Select: NM_032797 NM_001198696, NM_032797

CCDS: CCDS7297

Canonical transcript exons

ENST00000307864 — 9 exons

Exon	Start	End
ENSE00000933728	70114920	70115120
ENSE00000933729	70120507	70120599
ENSE00000933731	70123405	70123520
ENSE00001026958	70121092	70121211
ENSE00001186198	70123907	70124097
ENSE00001321771	70112271	70114329
ENSE00003596270	70116622	70116774
ENSE00003617467	70117812	70117920
ENSE00003847803	70132734	70132825

Expression profiles

Bgee: expression breadth ubiquitous, 214 present calls, max score 91.90.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.9553 / max 207.8727, expressed in 1536 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
109815	9.4952	1526
109813	0.1759	68
109814	0.1479	59
109816	0.1363	47

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adipose tissue	UBERON:0001013	91.90	gold quality
subcutaneous adipose tissue	UBERON:0002190	91.45	gold quality
adipose tissue of abdominal region	UBERON:0007808	90.38	gold quality
omental fat pad	UBERON:0010414	90.11	gold quality
peritoneum	UBERON:0002358	90.04	gold quality
mucosa of transverse colon	UBERON:0004991	90.04	gold quality
lower esophagus mucosa	UBERON:0035834	88.90	gold quality
apex of heart	UBERON:0002098	86.98	gold quality
heart left ventricle	UBERON:0002084	85.81	gold quality
right lobe of thyroid gland	UBERON:0001119	85.37	gold quality
cardiac ventricle	UBERON:0002082	85.37	gold quality
esophagus squamous epithelium	UBERON:0006920	84.84	gold quality
left coronary artery	UBERON:0001626	84.44	gold quality
left lobe of thyroid gland	UBERON:0001120	84.41	gold quality
transverse colon	UBERON:0001157	83.95	gold quality
right lobe of liver	UBERON:0001114	83.87	gold quality
left adrenal gland	UBERON:0001234	83.80	gold quality
coronary artery	UBERON:0001621	83.71	gold quality
right adrenal gland	UBERON:0001233	83.28	gold quality
thyroid gland	UBERON:0002046	83.19	gold quality
left adrenal gland cortex	UBERON:0035825	83.12	gold quality
heart	UBERON:0000948	83.03	gold quality
endothelial cell	CL:0000115	83.02	silver quality
thoracic mammary gland	UBERON:0005200	82.63	gold quality
mammary gland	UBERON:0001911	82.56	gold quality
esophagus mucosa	UBERON:0002469	82.41	gold quality
lower esophagus	UBERON:0013473	82.23	gold quality
popliteal artery	UBERON:0002250	82.21	gold quality
tibial artery	UBERON:0007610	82.21	gold quality
lower esophagus muscularis layer	UBERON:0035833	82.21	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.06

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP53

miRNA regulators (miRDB)

75 targeting AIFM2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248

Literature-anchored findings (GeneRIF, showing 27)

• induces caspase-independent apoptosis (PMID:11980907)
• encodes a homologue of the apoptosis-inducing factor (PMID:12135761)
• AMID is a p53-downstream gene involved in tumorigenesis. (PMID:15273740)
• Reasults establish a link between coenzyme and DNA binding that likely impacts on the physiological role of AMID in cellular apoptosis. (PMID:15958387)
• study of cellular localization of the endonuclease G, AIF & AMID during apoptosis using bioinformatics and image analysis (PMID:17347867)
• AIF-M2 lessens survival cell signaling in the presence of foreign (e.g. bacterial and (retro)viral) cytosolic DNA, thus contributing to the onset of apoptosis (PMID:17711848)
• HUHS1015 increased nuclear localization of apoptosis-inducing factor-homologous mitochondrion-associated inducer of death (AMID). (PMID:25244912)
• AIF and its family member protein, AMID, are rotenone-sensitive NADH:ubiquinone oxidoreductases (of the NDH-2 type). (PMID:26063804)
• AIF-2 was upregulated in human glioma tissues and cell lines. Downregulation of AIF-2 reduced cell proliferation and induced G1 cell cycle arrest. (PMID:30982162)
• AIFM2 (FSP1) confers protection against ferroptosis elicited by GPX4 deletion (PMID:31634899)
• identify FSP1 (previously known as AIFM2) as a key component of a non-mitochondrial CoQ antioxidant system that acts in parallel to the canonical glutathione-based GPX4 pathway (PMID:31634900)
• AIFM2 blocks ferroptosis independent of ubiquinol metabolism. (PMID:31964528)
• ATF6 aggravates acinar cell apoptosis and injury by regulating p53/AIFM2 transcription in Severe Acute Pancreatitis. (PMID:32724472)
• CircGFRA1 facilitates the malignant progression of HER-2-positive breast cancer via acting as a sponge of miR-1228 and enhancing AIFM2 expression. (PMID:34668628)
• Metabolic Intervention Nanoparticles for Triple-Negative Breast Cancer Therapy via Overcoming FSP1-Mediated Ferroptosis Resistance. (PMID:35395704)
• N-acetyltransferase 10 promotes colon cancer progression by inhibiting ferroptosis through N4-acetylation and stabilization of ferroptosis suppressor protein 1 (FSP1) mRNA. (PMID:36209353)
• HDLBP-stabilized lncFAL inhibits ferroptosis vulnerability by diminishing Trim69-dependent FSP1 degradation in hepatocellular carcinoma. (PMID:36423520)
• Elevated FSP1 protects KRAS-mutated cells from ferroptosis during tumor initiation. (PMID:36443441)
• Fear stress promotes glioma progression through inhibition of ferroptosis by enhancing FSP1 stability. (PMID:36484954)
• A genome-wide CRISPR-Cas9 knockout screen identifies FSP1 as the warfarin-resistant vitamin K reductase. (PMID:36788244)
• Molecular characterization of AIFM2/FSP1 inhibition by iFSP1-like molecules. (PMID:37080964)
• Phase separation of FSP1 promotes ferroptosis. (PMID:37380771)
• TRIM21-Promoted FSP1 Plasma Membrane Translocation Confers Ferroptosis Resistance in Human Cancers. (PMID:37587773)
• Ferroptosis of macrophages facilitates bone loss in apical periodontitis via NRF2/FSP1/ROS pathway. (PMID:37619958)
• Sorafenib induces ferroptosis by promoting TRIM54-mediated FSP1 ubiquitination and degradation in hepatocellular carcinoma. (PMID:37695069)
• YTHDC1 as a tumor progression suppressor through modulating FSP1-dependent ferroptosis suppression in lung cancer. (PMID:37903990)
• Circ0060467 sponges miR-6805 to promote hepatocellular carcinoma progression through regulating AIFM2 and GPX4 expression. (PMID:38244593)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	aifm2	ENSDARG00000077549
mus_musculus	Aifm2	ENSMUSG00000020085
rattus_norvegicus	Aifm2	ENSRNOG00000059445

Protein

Protein identifiers

Ferroptosis suppressor protein 1 — Q9BRQ8 (reviewed: Q9BRQ8)

Alternative names: Apoptosis-inducing factor homologous mitochondrion-associated inducer of death, p53-responsive gene 3 protein

All UniProt accessions (1): Q9BRQ8

UniProt curated annotations — full annotation on UniProt →

Function. A NAD(P)H-dependent oxidoreductase that acts as a key inhibitor of ferroptosis. At the plasma membrane, catalyzes reduction of coenzyme Q/ubiquinone-10 to ubiquinol-10, a lipophilic radical-trapping antioxidant that prevents lipid oxidative damage and consequently ferroptosis. Acts in parallel to GPX4 to suppress phospholipid peroxidation and ferroptosis. This anti-ferroptotic function is independent of cellular glutathione levels. Also acts as a potent radical-trapping antioxidant by mediating warfarin-resistant vitamin K reduction in the canonical vitamin K cycle: catalyzes NAD(P)H-dependent reduction of vitamin K (phylloquinone, menaquinone-4 and menadione) to hydroquinone forms. Hydroquinones act as potent radical-trapping antioxidants inhibitor of phospholipid peroxidation and ferroptosis. May play a role in mitochondrial stress signaling. Upon oxidative stress, associates with the lipid peroxidation end product 4-hydroxy-2-nonenal (HNE) forming a lipid adduct devoid of oxidoreductase activity, which then translocates from mitochondria into the nucleus triggering DNA damage and cell death. Capable of DNA binding in a non-sequence specific way.

Subunit / interactions. Interacts with importin subunits KPNA2 and IPO5; this interaction likely mediates the translocation into the nucleus upon oxidative stress.

Subcellular location. Lipid droplet. Cell membrane. Cytoplasm. Mitochondrion membrane. Nucleus.

Tissue specificity. Detected in most normal tissues as two transcripts of 1.8 and 4.0 kb in length, respectively. Highly expressed in heart, moderately in liver and skeletal muscles, and expressed at low levels in placenta, lung, kidney, and pancreas. Both transcripts expressed following p53/TP53 induction. The shorter 1.8 kb transcript seems to be the major transcript in EB1 colon cancer cells.

Post-translational modifications. N-myristoylation at Gly-2 mediates the recruitment to lipid droplets and plasma membrane, enabling its anti-lipid peroxidation activity. Acetylation at Lys-168 prevents AIFM2 ubiquitination and degradation, thereby inhibiting ferroptosis. KAT2B mediates acetylation at Lys-168, while HDAC3 removes it. Ubiquitinated. AIFM2 undergoes ‘Lys-29’-ubiquitination and proteasomal degradation, which is inhibited by acetylation at Lys-168.

Activity regulation. The modification by 4-hydroxy-2-nonenal (HNE) adduction in mitochondria results in loss of the oxidoreductase activity and activation of a novel function in mitochondrial oxidative stress signaling. NADH-dependent oxidoreductase activity in response to ferroptotic stress is supported by ALDH7A1, which generates membrane NADH required for AIFM2/FSP1 activity. Inhibited by iFSP1; a species-specific inhibitor that targets the quinone-binding site, and which does not inhibit mouse AIFM2/FSP1. Inhibited by viFSP1, which targets the NAD(P)H-binding pocket. Strongly inhibited by 3-phenylquinazolinone icFSP1, which promotes AIFM2/FSP1 liquid-liquid phase separation into liquid droplets and relocalization from the membrane into condensates, triggerring ferroptosis.

Cofactor. Binds 6-hydroxy-FAD non-covalently.

Induction. Expression detected at 4 hours after induction by p53/TP53. Down-regulated in a wide range of human tumors.

Similarity. Belongs to the FAD-dependent oxidoreductase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BRQ8-1	1	yes
Q9BRQ8-2	2

RefSeq proteins (2): NP_001185625, NP_116186* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR023753	FAD/NAD-binding_dom	Domain
IPR036188	FAD/NAD-bd_sf	Homologous_superfamily

Pfam: PF07992

Enzyme classification (BRENDA):

• EC 7.1.1.2 — NADH:ubiquinone reductase (H+-translocating) (BRENDA: 58 organisms, 186 substrates, 276 inhibitors, 132 Km, 34 kcat entries)

Substrate kinetics (BRENDA)

38 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
NADH	0.0001–1.1	41
DECYLUBIQUINONE	0.024–43	9
N-DECYLUBIQUINONE	0.007–0.039	8
UBIQUINONE-1	0.002–0.4	7
NADPH	0.025–1.87	6
COENZYME Q1	0.01–0.024	5
UBIQUINONE-2	0.0032–0.083	5
FERRICYTOCHROME C	0.012–0.0684	4
MENADIONE	0.002–0.239	4
FERRICYANIDE	0.055–4	3
NAD+	0.007–0.27	3
OXIDIZED 2,6-DICHLOROPHENOLINDOPHENOL	0.0062–0.55	3
UBIQUINONE-0	0.104–0.35	3
1,1’-CARBAMOYLMETHYLVIOLOGEN	0.55–1	2
MENAQUINONE	0.1	2

Catalyzed reactions (Rhea), 5 shown:

• ubiquinone-10 + NADPH + H(+) = ubiquinol-10 + NADP(+) (RHEA:61980)
• ubiquinone-10 + NADH + H(+) = ubiquinol-10 + NAD(+) (RHEA:61984)
• menadione + NADH + H(+) = menadiol + NAD(+) (RHEA:69695)
• phylloquinone + NADH + H(+) = phylloquinol + NAD(+) (RHEA:74075)
• menaquinone-4 + NADH + H(+) = menaquinol-4 + NAD(+) (RHEA:74079)

UniProt features (81 total): binding site 41, mutagenesis site 30, splice variant 2, sequence variant 2, initiator methionine 1, chain 1, transmembrane region 1, site 1, modified residue 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
8YOQ	X-RAY DIFFRACTION	1.79
8WIK	X-RAY DIFFRACTION	2
8YO8	X-RAY DIFFRACTION	2
9M3M	X-RAY DIFFRACTION	2.01
8JSC	X-RAY DIFFRACTION	2.16
8YOX	X-RAY DIFFRACTION	2.48

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BRQ8-F1	95.79	0.95

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 (1): 174 (4-hydroxy-2-nonenal adduction)

Ligand- & substrate-binding residues (41): 111; 118; 120; 152; 153; 153; 153; 156; 156; 175; 175; 176 …

Post-translational modifications (2): 168, 2

Mutagenesis-validated functional residues (30):

Position	Phenotype
2	impairs n-myristoylation and ferroptosis suppression. abolished ability to form liquid-liquid phase separation upon bind
18	decreased nad(p)h-dependent oxidoreductase activity.
20	abolished nad(p)h-dependent oxidoreductase activity.
21	decreased nad(p)h-dependent oxidoreductase activity.
43	does not affect ability to inhibit ferroptosis.
48	induces resistance to ifsp1 and vifsp1 inhibitors.
49	reduced oxidoreductase activity.
82	slightly reduced binding to nadh.
149	decreased nad(p)h-dependent oxidoreductase activity.
151	decreased nad(p)h-dependent oxidoreductase activity.
152	strongly reduced binding to 6-hydroxy-fad cofactor.
153	increased sensitivity to vifsp1 inhibitor.
156	abolished binding to 6-hydroxy-fad cofactor, leading to impaired nad(p)h-dependent oxidoreductase activity.
160	decreased ability to inhibit ferroptosis.
164	does not affect ability to inhibit ferroptosis.
168	acetylation-mimetic. results in reduced ubiquitination and increased stability of the protein.
168	no acetylation at this site. results in increased ubiquitination and reduced stability of the protein. loss of function
174	reduced binding to nadh.
175–176	impaired binding with nadph without affecting binding to nadh; when associated with p-208.
187	abolished ability to form liquid-liquid phase separation upon binding to 3-phenylquinazolinone icfsp1.
208	impaired binding with nadph without affecting binding to nadh; when associated with 175-a-a-176.
217	abolished ability to form liquid-liquid phase separation upon binding to 3-phenylquinazolinone icfsp1.
244	abolished nad(p)h-dependent oxidoreductase activity.
285	abolished nad(p)h-dependent oxidoreductase activity.
294	induces resistance to vifsp1 inhibitor.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6803204	TP53 Regulates Transcription of Genes Involved in Cytochrome C Release

MSigDB gene sets: 235 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_INTERLEUKIN_8_PRODUCTION, GOCC_SECRETORY_GRANULE, GOBP_SUPEROXIDE_METABOLIC_PROCESS, DARWICHE_SKIN_TUMOR_PROMOTER_UP, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_UP, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, DARWICHE_SQUAMOUS_CELL_CARCINOMA_UP, GOBP_LEUKOTRIENE_BIOSYNTHETIC_PROCESS, GOBP_KETONE_METABOLIC_PROCESS, GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_BLUE_UP, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_TRANSLATION, GOBP_TRANSLATION

GO Biological Process (8): ubiquinone metabolic process (GO:0006743), apoptotic mitochondrial changes (GO:0008637), vitamin K metabolic process (GO:0042373), positive regulation of apoptotic process (GO:0043065), negative regulation of ferroptosis (GO:0110076), regulation of cellular response to oxidative stress (GO:1900407), cellular detoxification (GO:1990748), respiratory electron transport chain (GO:0022904)

GO Molecular Function (6): DNA binding (GO:0003677), electron-transferring-flavoprotein dehydrogenase activity (GO:0004174), oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor (GO:0016655), flavin adenine dinucleotide binding (GO:0050660), protein binding (GO:0005515), oxidoreductase activity (GO:0016491)

GO Cellular Component (10): obsolete extracellular space (GO:0005615), nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), lipid droplet (GO:0005811), cytosol (GO:0005829), plasma membrane (GO:0005886), mitochondrial membrane (GO:0031966), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
TP53 Regulates Transcription of Cell Death Genes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
apoptotic process	2
intracellular membrane-bounded organelle	2
cytoplasm	2
quinone metabolic process	1
mitochondrion organization	1
ketone metabolic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
negative regulation of programmed cell death	1
ferroptosis	1
regulation of ferroptosis	1
cellular response to oxidative stress	1
regulation of cellular response to stress	1
regulation of response to oxidative stress	1
cellular process	1
cellular response to toxic substance	1
detoxification	1
electron transport chain	1
cellular respiration	1
nucleic acid binding	1
electron transfer activity	1
oxidoreductase activity, acting on the CH-NH group of donors, quinone or similar compound as acceptor	1
respiratory electron transport chain	1
oxidoreductase activity, acting on NAD(P)H	1
nucleotide binding	1
anion binding	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
mitochondrial membrane	1
organelle outer membrane	1
intracellular membraneless organelle	1
membrane	1
cell periphery	1
mitochondrion	1
mitochondrial envelope	1
organelle membrane	1

Protein interactions and networks

STRING

2273 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AIFM2	GPX4	P36969	810
AIFM2	GADD45GIP1	Q8TAE8	766
AIFM2	TP53	P04637	708
AIFM2	ACSL4	O60488	700
AIFM2	LPCAT3	Q6P1A2	664
AIFM2	SLC7A11	Q9UPY5	664
AIFM2	SLC3A2	P08195	613
AIFM2	DHODH	Q02127	597
AIFM2	NCOA4	Q13772	580
AIFM2	SLC11A2	P49281	554
AIFM2	ACSF2	Q96CM8	542
AIFM2	FTH1	P02794	538
AIFM2	STEAP3	Q658P3	534
AIFM2	AIFM1	O95831	510
AIFM2	CYCS	P00001	507
AIFM2	GCH1	P30793	507

IntAct

29 interactions, top by confidence:

A	B	Type	Score
USE1	NBAS	psi-mi:“MI:0914”(association)	0.640
AIFM2	TRIM54	psi-mi:“MI:0915”(physical association)	0.560
TRIM69	AIFM2	psi-mi:“MI:0915”(physical association)	0.560
CNPY4	AIFM2	psi-mi:“MI:0915”(physical association)	0.560
NMES1	COX7A2L	psi-mi:“MI:0914”(association)	0.350
COQ9	ACOT7	psi-mi:“MI:0914”(association)	0.350
NDUFA4	NDUFS8	psi-mi:“MI:0914”(association)	0.350
COQ9	NDUFS8	psi-mi:“MI:0914”(association)	0.350
NDUFA4	COX7A2L	psi-mi:“MI:0914”(association)	0.350
P		psi-mi:“MI:0914”(association)	0.350
MYC		psi-mi:“MI:0914”(association)	0.350
AIFM2	PPP2CA	psi-mi:“MI:0914”(association)	0.350
AIFM2	NMT2	psi-mi:“MI:0914”(association)	0.350
IQUB	DUSP14	psi-mi:“MI:0914”(association)	0.350
AFG2A	ESYT2	psi-mi:“MI:0914”(association)	0.350
P4HA3	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
SAAL1	TMEM223	psi-mi:“MI:0914”(association)	0.350
SLC1A3	DDX11L8	psi-mi:“MI:0914”(association)	0.350
SLC2A3	NRP2	psi-mi:“MI:0914”(association)	0.350
ATF2	ABLIM1	psi-mi:“MI:0914”(association)	0.350
ERBB2	AGPS	psi-mi:“MI:0914”(association)	0.350
STAT3	NACA	psi-mi:“MI:0914”(association)	0.350
AIFM2	TRIM69	psi-mi:“MI:0915”(physical association)	0.000
AIFM2	TRIM54	psi-mi:“MI:0915”(physical association)	0.000
AIFM2	CNPY4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (54): AIFM2 (Affinity Capture-MS), TRIM54 (Two-hybrid), CNPY4 (Two-hybrid), TRIM69 (Two-hybrid), AIFM2 (Proximity Label-MS), AIFM2 (Proximity Label-MS), AIFM2 (Proximity Label-MS), AIFM2 (Affinity Capture-RNA), AIFM2 (Affinity Capture-MS), AIFM2 (Affinity Capture-MS), AIFM2 (Proximity Label-MS), ECHDC1 (Affinity Capture-MS), CDR2 (Affinity Capture-MS), SPECC1L (Affinity Capture-MS), SESTD1 (Affinity Capture-MS)

ESM2 similar proteins: A0PJE2, A5PJM4, A7YVH9, B4F6I3, B5FXE5, D3ZDM7, D4A2H2, O15269, O35296, O35469, O35704, O54695, O64489, O88736, P09367, P11172, P13439, P20132, P24815, P26439, P31228, P31754, P56937, Q2KIJ5, Q3TMV7, Q3TY86, Q5R514, Q5R9T5, Q5REJ2, Q60555, Q60HD1, Q62904, Q64421, Q68FS6, Q6GLW8, Q6IQS6, Q6PBT5, Q80SY6, Q8BUE4, Q8CCT7

Diamond homologs: A5PJM4, B4F6I3, B5FXE5, Q2RBS5, Q54NS8, Q54NS9, Q6GLW8, Q8BUE4, Q9BRQ8, Q1JPL4, Q9I1S2, Q51973, D5IGG6, G9F1Y9, O58308, P11959, P37061, P37062, Q42711, Q58065, Q5JGP4, Q8U1M0, Q9LK94, Q9UYU5

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
TP53	“up-regulates quantity by expression”	AIFM2	“transcriptional regulation”
AIFM2	up-regulates	Apoptosis

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	76
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2907 predictions. Top by Δscore:

Variant	Effect	Δscore
10:70109024:A:AG	acceptor_gain	1.0000
10:70109025:T:G	acceptor_gain	1.0000
10:70109203:GGCAG:G	donor_gain	1.0000
10:70109204:GCAG:G	donor_gain	1.0000
10:70109204:GCAGG:G	donor_gain	1.0000
10:70109207:GGT:G	donor_loss	1.0000
10:70109208:G:GA	donor_loss	1.0000
10:70109209:T:A	donor_loss	1.0000
10:70111510:T:TA	acceptor_gain	1.0000
10:70111515:C:G	acceptor_gain	1.0000
10:70111516:A:AG	acceptor_gain	1.0000
10:70111517:G:GG	acceptor_gain	1.0000
10:70111517:GA:G	acceptor_gain	1.0000
10:70111517:GAA:G	acceptor_gain	1.0000
10:70111517:GAAAC:G	acceptor_gain	1.0000
10:70114327:CAC:C	acceptor_gain	1.0000
10:70114327:CACCT:C	acceptor_loss	1.0000
10:70114328:AC:A	acceptor_gain	1.0000
10:70114328:ACCT:A	acceptor_loss	1.0000
10:70114329:CC:C	acceptor_gain	1.0000
10:70114329:CCTG:C	acceptor_loss	1.0000
10:70114330:C:A	acceptor_loss	1.0000
10:70114330:C:CC	acceptor_gain	1.0000
10:70114331:T:G	acceptor_loss	1.0000
10:70114337:C:CT	acceptor_gain	1.0000
10:70114916:TTA:T	donor_loss	1.0000
10:70114917:TACC:T	donor_loss	1.0000
10:70114918:A:AC	donor_gain	1.0000
10:70114918:AC:A	donor_gain	1.0000
10:70114918:ACC:A	donor_gain	1.0000

AlphaMissense

2422 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:70124022:A:C	F21L	0.996
10:70124022:A:T	F21L	0.996
10:70124024:A:G	F21L	0.996
10:70114235:C:A	K355N	0.994
10:70114235:C:G	K355N	0.994
10:70121192:A:G	L105P	0.994
10:70115045:G:T	A282D	0.993
10:70116665:G:C	C242W	0.993
10:70124005:G:T	A27D	0.993
10:70124018:C:A	G23W	0.993
10:70115032:A:C	C286W	0.992
10:70115036:T:A	D285V	0.992
10:70115039:C:A	G284V	0.992
10:70115075:A:G	L272P	0.992
10:70121189:A:T	I106N	0.991
10:70121200:G:C	F102L	0.991
10:70121200:G:T	F102L	0.991
10:70121202:A:G	F102L	0.991
10:70124006:C:G	A27P	0.991
10:70124032:C:T	G18D	0.991
10:70115036:T:C	D285G	0.990
10:70121184:C:G	A108P	0.990
10:70114303:C:A	G333W	0.989
10:70120539:C:G	A159P	0.989
10:70123947:G:C	F46L	0.989
10:70123947:G:T	F46L	0.989
10:70123949:A:G	F46L	0.989
10:70123996:A:G	L30P	0.989
10:70114284:C:T	G339D	0.988
10:70114302:C:A	G333V	0.988

dbSNP variants (sampled 300 via entrez): RS1000016694 (10:70132322 A>C), RS1000237937 (10:70121012 T>C), RS1000452802 (10:70132487 A>C), RS1000523973 (10:70126943 C>A), RS1000541031 (10:70119873 C>T), RS1000789850 (10:70121301 C>G,T), RS1000971288 (10:70125756 C>A,G), RS1000996490 (10:70132337 C>T), RS1001168341 (10:70113794 T>C), RS1001188917 (10:70114389 C>T), RS1001203267 (10:70123912 T>C,G), RS1001220795 (10:70120984 G>A,T), RS1001422111 (10:70133359 A>G), RS1001447593 (10:70118207 T>C), RS1001539959 (10:70125259 G>T)

Disease associations

OMIM: gene MIM:605159 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001438_11	Crohn’s disease	8.000000e-09
GCST003264_906	Post bronchodilator FEV1/FVC ratio	1.000000e-06
GCST007843_20	Rheumatoid arthritis	4.000000e-08
GCST90002381_298	Eosinophil count	5.000000e-14
GCST90002382_382	Eosinophil percentage of white cells	2.000000e-15

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067200 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.59	Kd	2.582	nM	CHEMBL5653589
8.59	ED50	2.582	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147824: Binding affinity to human AIFM2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0026	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, affects cotreatment, increases abundance	5
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	4
bisphenol A	increases abundance, affects expression, decreases expression, increases expression, decreases reaction	3
Cisplatin	increases expression, increases reaction, decreases expression, affects reaction, decreases reaction (+1 more)	3
Cyclosporine	increases expression	3
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
Acetaminophen	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Tobacco Smoke Pollution	increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
bisphenol F	increases expression	1
ginger extract	decreases reaction, increases abundance, decreases expression	1
chloroacetaldehyde	increases expression	1
triphenyl phosphate	affects expression	1
lead acetate	increases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
ochratoxin A	decreases expression, increases reaction, decreases reaction	1
nickel monoxide	decreases expression, increases reaction	1
cupric chloride	increases expression	1
hydroquinone	increases expression	1
cadmium sulfide	increases expression	1
osthol	decreases expression, increases reaction	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
1-(2-(3,4-dichlorophenyl)ethyl)-4-methylpiperazine	increases reaction, decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5650866	Binding	Binding affinity to human AIFM2 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7JW	Ubigene A-549 AIFM2 KO	Cancer cell line	Male
CVCL_D9WD	Ubigene HT-1080 AIFM2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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