TIGAR

Summary

TIGAR (TP53 induced glycolysis regulatory phosphatase, HGNC:1185) is a protein-coding gene on chromosome 12p13.32, encoding Fructose-2,6-bisphosphatase TIGAR (Q9NQ88). Fructose-bisphosphatase hydrolyzing fructose-2,6-bisphosphate as well as fructose-1,6-bisphosphate.

This gene is regulated as part of the p53 tumor suppressor pathway and encodes a protein with sequence similarity to the bisphosphate domain of the glycolytic enzyme that degrades fructose-2,6-bisphosphate. The protein functions by blocking glycolysis and directing the pathway into the pentose phosphate shunt. Expression of this protein also protects cells from DNA damaging reactive oxygen species and provides some protection from DNA damage-induced apoptosis. The 12p13.32 region that includes this gene is paralogous to the 11q13.3 region.

Source: NCBI Gene 57103 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 32 total
• Druggable target: yes
• MANE Select transcript: NM_020375

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1185
Approved symbol	TIGAR
Name	TP53 induced glycolysis regulatory phosphatase
Location	12p13.32
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000078237
Ensembl biotype	protein_coding
OMIM	610775
Entrez	57103

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000179259, ENST00000537251, ENST00000539671, ENST00000635110, ENST00000859882

RefSeq mRNA: 1 — MANE Select: NM_020375 NM_020375

CCDS: CCDS8525

Canonical transcript exons

ENST00000179259 — 6 exons

Exon	Start	End
ENSE00000997495	4331280	4331317
ENSE00001158066	4352260	4360028
ENSE00001430794	4321213	4321303
ENSE00003565950	4337039	4337160
ENSE00003579655	4351267	4351377
ENSE00003680979	4349819	4349896

Expression profiles

Bgee: expression breadth ubiquitous, 140 present calls, max score 84.97.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.3163 / max 221.5980, expressed in 1730 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
123556	14.2349	1730
123557	0.0447	6
123558	0.0366	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	84.97	gold quality
stromal cell of endometrium	CL:0002255	84.91	gold quality
leukocyte	CL:0000738	84.56	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.33	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.40	gold quality
skeletal muscle tissue	UBERON:0001134	81.30	gold quality
muscle tissue	UBERON:0002385	78.43	gold quality
gastrocnemius	UBERON:0001388	78.18	gold quality
right adrenal gland cortex	UBERON:0035827	78.10	gold quality
granulocyte	CL:0000094	78.05	gold quality
skeletal muscle organ	UBERON:0014892	77.73	gold quality
placenta	UBERON:0001987	77.67	gold quality
islet of Langerhans	UBERON:0000006	77.64	gold quality
muscle of leg	UBERON:0001383	77.59	gold quality
superior frontal gyrus	UBERON:0002661	77.48	gold quality
prefrontal cortex	UBERON:0000451	77.15	gold quality
corpus callosum	UBERON:0002336	76.81	gold quality
cortical plate	UBERON:0005343	76.04	gold quality
mucosa of stomach	UBERON:0001199	75.93	gold quality
hindlimb stylopod muscle	UBERON:0004252	75.88	gold quality
right adrenal gland	UBERON:0001233	75.42	gold quality
left adrenal gland	UBERON:0001234	75.42	gold quality
vermiform appendix	UBERON:0001154	75.24	gold quality
lymph node	UBERON:0000029	75.23	gold quality
endometrium	UBERON:0001295	75.05	gold quality
colonic epithelium	UBERON:0000397	74.73	gold quality
adrenal gland	UBERON:0002369	74.59	gold quality
primary visual cortex	UBERON:0002436	74.45	gold quality
blood	UBERON:0000178	74.43	gold quality
adenohypophysis	UBERON:0002196	74.35	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.59

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, HIF1A, SP1, TP53

miRNA regulators (miRDB)

246 targeting TIGAR, 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-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775

Literature-anchored findings (GeneRIF, showing 40)

• The decrease of intracellular ROS levels in response to TIGAR may also play a role in the ability of p53 to protect from the accumulation of genomic damage. (PMID:16839880)
• correlation between the recently described p53-inducible apoptosis gene TIGAR and both sensitivity to fludarabine and hENT2 expression in chronic lymphocytic leukemia cells. (PMID:18945750)
• TIGAR can modulate reactive oxygen species in response to nutrient starvation or metabolic stress, and functions to inhibit autophagy. (PMID:19713938)
• Inhibition of TIGAR by c-Met results in reduction of cellular NADPH and cell death. (PMID:21057531)
• SP1 can interact with the SP1-binding site within TIGAR promoter in vitro and in vivo. Conclusively, SPl is indispensable for basal activity of TIGAR promoter. (PMID:21761199)
• These results suggest that p53 can modulate the metabolic pathways via the proteins SCO2 and TIGAR in human breast cancer. (PMID:21820150)
• TIGAR abrogation provides a novel adjunctive therapeutic strategy against glial tumors by increasing radiation-induced cell impairment, thus allowing the use of lower radiotherapeutic doses. (PMID:21864926)
• TIGAR regulates the expression of genes involved in cell-cycle progression. (PMID:22782351)
• Tp53-induced glycolysis and apoptosis regulator (TIGAR) protects glioma cells from starvation-induced cell death by up-regulating respiration and improving cellular redox homeostasis (PMID:22887998)
• The ability of TIGAR to function as a Fru-2,6-BPase was independent of hexokinase 2 binding and mitochondrial localization, although activities can contribute to the activity of TIGAR in limiting mitochondrial ROS levels and protecting from cell death. (PMID:23185017)
• oroxylin A could increase protein and mRNA expression of TP53-induced glycolysis and apoptosis regulator (TIGAR) and synthesis of cytochrome c oxidase 2 (SCO2), which are the key metabolic modulators regulated by p53. (PMID:23612020)
• TIGAR regulates akt and erk phosphorylation but hase no effect on NF-kappa B activation in neocazinostatin-treated cells. (PMID:23640457)
• TIGAR has roles in efficient intestinal regeneration and tumorigenesis (PMID:23726973)
• data provide the first evidence that targeted silencing of TIGAR induces apoptotic and autophagic cell death in HepG2 cells (PMID:23817040)
• TIGAR gene expression is down regulated by oxidative stress through the mediation of reactive oxygen species (PMID:23832602)
• CREB regulates TIGAR expression via a CRE-binding site at the TIGAR promoter. (PMID:24036271)
• TIGAR is correlated with maximal standardized uptake value on FDG-PET and survival in non-small cell lung cancer. (PMID:24363807)
• The kinetic properties and the structural similarity of the best substrates of TIGAR make it unlikely that TIGAR modulates cellular fructose 2,6-bisphosphate levels directly. (PMID:24423178)
• Data show targeting MUC1-C is synergistic with bortezomib (BTZ) in suppressing p53-inducible regulator of glycolysis and apoptosis (TIGAR)-mediated regulation of reactive oxygen species levels for combining GO-203 with BTZ in BTZ resistance. (PMID:24632713)
• Results revealed that TIGAR inhibits both apoptosis and autophagy. (PMID:25085248)
• miR-144 targeted TIGAR, inhibited proliferation, enhanced apoptosis, and increased autophagy in A549 and H460 cells (PMID:25660220)
• The Cdk5-AMT signal pathway involved in regulation of DDR by TIGAR. (PMID:25928429)
• TIGAR over-expression could diminish the radiosensitivity of Hs 917.T cells, and the autophagy level induced by ionizing radiation (IR) was also decreased by TIGAR transfection. (PMID:26191173)
• TIGAR expression may be used as a bio-marker for detection of colorectal cancer and can be used as a target for developing therapeutics for the treatment of colorectal cancer. (PMID:26675982)
• TIGAR knockdown reduced tumor growth rate. (PMID:26691054)
• Geranylgeranoic acid induced upregulation of the TIGAR gene, which might inhibit the glycolysis in HuH-7 cells with p53 mutation. (PMID:26700591)
• we investigate the crosstalk between PFKFB3 and TIGAR (TP53-Induced Glycolysis and Apoptosis Regulator), a protein known to protect cells from oxidative stress. Our results show consistent TIGAR induction in HeLa cells in response to PFKFB3 knockdown (PMID:27491040)
• This study demonstrated that a high p53 expression could be associated with the promotion of glycolysis in gastric cancer via the modulation of TIGAR expression. (PMID:27499152)
• simultaneous mutations at all four acetylation sites completely abolish its ability to regulate metabolic targets, such as TIGAR and SLC7A11. Moreover, p53(4KR) is still capable of inducing the p53-Mdm2 feedback loop, but p53-dependent ferroptotic responses are markedly abrogated (PMID:27705786)
• TIGAR expression in breast carcinoma cells promotes metabolic compartmentalization and tumor growth with a mitochondrial metabolic phenotype with lactate and glutamine catabolism. (PMID:27803158)
• High TIGAR expression was an independent predictor of poor survival and high incidence of relapse in adult patients with CN-AML. TIGAR also showed high expression in multiple human leukemia cell lines and knockdown of TIGAR activated glycolysis through PFKFB3 upregulation in human leukemia cells. (PMID:27884166)
• the upregulation of hsamiR101 in ccRCC was induced by hypoxia. Its expression deceased the protein expression of TIGAR and promoted glycolysis. This regulatory pathway may represent a novel mechanism of carcinogenesis and requires further investigation. (PMID:28138701)
• Knockdown of TP53 induced glycolysis and apoptosis(TIGAR) was able to radiosensitize thioredoxin reductase-1-overexpressing gliomas by inhibiting irradiation -induced thioredoxin-1 nuclear transport. (PMID:28338004)
• The study showed that miR-101 inhibited viability, induced apoptosis, pushed glucose metabolism flux from the pentose phosphate pathway into glycolysis in prostate cancer PC3 cell line by decreasing NADPH levels by throughly directly binding to 3’-UTR of TIGAR mRNA and repressing TIGAR expression. (PMID:28384067)
• Study found that downregulation of TIGAR reduced the invasion and metastasis of non-small-cell lung cancer (NSCLC) cells in vitro and in vivo. TIGAR and Met protein expression was positively correlated with late stages of lung cancer. Patients with high co-expression of TIGAR and Met presented a significantly worse survival. In addition, Met signaling pathway is involved in TIGAR-induced invasion and metastasis. (PMID:29753331)
• findings demonstrate that the HTLV-1 latency-maintenance factor p30(II) induces the TP53-induced glycolysis and apoptosis regulator (TIGAR) and counters the oxidative stress, mitochondrial damage, and cytotoxicity caused by the viral oncoproteins Tax and HBZ (PMID:29777913)
• TIGAR protein, is present in SN Lewy bodies of both sporadic PD and DLB. The absence of TIGAR protein in the pathological inclusions of MND or MSA suggests disease specificity and further raises the possibility that TIGAR may be involved in PD pathogenesis. (PMID:30267647)
• TIGAR promotes metabolic reprogramming and regulates NSC differentiation through an epigenetic mechanism. (PMID:30814486)
• TIGAR knockdown enhanced glioma cell sensitivity to cell hypoxia, irradiation and temozolomide. (PMID:30823646)
• Down-regulation of TFAM increases the sensitivity of tumour cells to radiation via p53/TIGAR signalling pathway. (PMID:31062473)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tigar	ENSMUSG00000038028
rattus_norvegicus	Tigar	ENSRNOG00000051816

Protein

Protein identifiers

Fructose-2,6-bisphosphatase TIGAR — Q9NQ88 (reviewed: Q9NQ88)

Alternative names: TP53-induced glycolysis and apoptosis regulator, TP53-induced glycolysis regulatory phosphatase

All UniProt accessions (2): Q9NQ88, A0A0U1RQD1

UniProt curated annotations — full annotation on UniProt →

Function. Fructose-bisphosphatase hydrolyzing fructose-2,6-bisphosphate as well as fructose-1,6-bisphosphate. Acts as a negative regulator of glycolysis by lowering intracellular levels of fructose-2,6-bisphosphate in a p53/TP53-dependent manner, resulting in the pentose phosphate pathway (PPP) activation and NADPH production. Contributes to the generation of reduced glutathione to cause a decrease in intracellular reactive oxygen species (ROS) content, correlating with its ability to protect cells from oxidative or metabolic stress-induced cell death. Plays a role in promoting protection against cell death during hypoxia by decreasing mitochondria ROS levels in a HK2-dependent manner through a mechanism that is independent of its fructose-bisphosphatase activity. In response to cardiac damage stress, mediates p53-induced inhibition of myocyte mitophagy through ROS levels reduction and the subsequent inactivation of BNIP3. Reduced mitophagy results in an enhanced apoptotic myocyte cell death, and exacerbates cardiac damage. Plays a role in adult intestinal regeneration; contributes to the growth, proliferation and survival of intestinal crypts following tissue ablation. Plays a neuroprotective role against ischemic brain damage by enhancing PPP flux and preserving mitochondria functions. Protects glioma cells from hypoxia- and ROS-induced cell death by inhibiting glycolysis and activating mitochondrial energy metabolism and oxygen consumption in a TKTL1-dependent and p53/TP53-independent manner. Plays a role in cancer cell survival by promoting DNA repair through activating PPP flux in a CDK5-ATM-dependent signaling pathway during hypoxia and/or genome stress-induced DNA damage responses. Involved in intestinal tumor progression.

Subunit / interactions. Interacts with HK2; the interaction increases hexokinase HK2 activity in a hypoxia- and HIF1A-dependent manner, resulting in the regulation of mitochondrial membrane potential, thus increasing NADPH production and decreasing intracellular ROS levels.

Subcellular location. Cytoplasm. Nucleus. Mitochondrion.

Tissue specificity. Expressed in the brain. Expressed in breast tumors. Expressed in glioblastomas.

Induction. Up-regulated by p53/TP53 (at protein level). Rapidly up-regulated by p53/TP53. Up-regulated in glioma cell line in a p53/TP53-independent manner.

Similarity. Belongs to the phosphoglycerate mutase family.

RefSeq proteins (1): NP_065108* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001345	PG/BPGM_mutase_AS	Active_site
IPR013078	His_Pase_superF_clade-1	Family
IPR029033	His_PPase_superfam	Homologous_superfamily
IPR051695	Phosphoglycerate_Mutase	Family

Pfam: PF00300

Catalyzed reactions (Rhea), 1 shown:

• beta-D-fructose 2,6-bisphosphate + H2O = beta-D-fructose 6-phosphate + phosphate (RHEA:17289)

UniProt features (29 total): helix 10, strand 8, mutagenesis site 4, active site 2, turn 2, chain 1, site 1, modified residue 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3DCY	X-RAY DIFFRACTION	1.75

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NQ88-F1	90.00	0.78

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 (3): 11 (tele-phosphohistidine intermediate); 89 (proton donor/acceptor); 198 (transition state stabilizer)

Post-translational modifications (1): 50

Mutagenesis-validated functional residues (4):

Position	Phenotype
11	abolishes the ability to lower cellular fructose-2,6-bisphosphate levels, to inhibit the glycolytic activity, to reduce
102	abolishes the ability to lower cellular fructose-2,6-bisphosphate levels, to inhibit the glycolytic activity, to reduce
198	abolishes the ability to lower cellular fructose-2,6-bisphosphate levels, to inhibit the glycolytic activity, to reduce
258–261	inhibits the ability to interact and enhance hk2 activity, to localize to the mitochondria, to protect against the decre

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-5628897	TP53 Regulates Metabolic Genes
R-HSA-212436	Generic Transcription Pathway
R-HSA-3700989	Transcriptional Regulation by TP53
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)

MSigDB gene sets: 294 (showing top): ELVIDGE_HYPOXIA_DN, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, MYOGENIN_Q6, E2F4DP1_01, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_NADPPLUS_METABOLIC_PROCESS, GCANCTGNY_MYOD_Q6, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_NEGATIVE_REGULATION_OF_REACTIVE_OXYGEN_SPECIES_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS

GO Biological Process (30): mitophagy (GO:0000423), response to ischemia (GO:0002931), fructose 2,6-bisphosphate metabolic process (GO:0006003), glycolytic process (GO:0006096), DNA damage response (GO:0006974), response to xenobiotic stimulus (GO:0009410), response to gamma radiation (GO:0010332), cardiac muscle cell apoptotic process (GO:0010659), positive regulation of cardiac muscle cell apoptotic process (GO:0010666), obsolete homolactic fermentation (GO:0019661), negative regulation of programmed cell death (GO:0043069), regulation of pentose-phosphate shunt (GO:0043456), positive regulation of DNA repair (GO:0045739), negative regulation of glycolytic process (GO:0045820), intestinal epithelial cell development (GO:0060576), cellular response to cobalt ion (GO:0071279), cellular response to hypoxia (GO:0071456), reactive oxygen species metabolic process (GO:0072593), negative regulation of mitophagy (GO:1901525), regulation of response to DNA damage checkpoint signaling (GO:1902153), positive regulation of hexokinase activity (GO:1903301), negative regulation of glucose catabolic process to lactate via pyruvate (GO:1904024), positive regulation of pentose-phosphate shunt (GO:1905857), negative regulation of reactive oxygen species metabolic process (GO:2000378), autophagy (GO:0006914), apoptotic process (GO:0006915), response to stress (GO:0006950), regulation of programmed cell death (GO:0043067), obsolete positive regulation of nucleobase-containing compound metabolic process (GO:0045935), positive regulation of phosphate metabolic process (GO:0045937)

GO Molecular Function (4): fructose-2,6-bisphosphate 2-phosphatase activity (GO:0004331), catalytic activity (GO:0003824), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (5): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrial outer membrane (GO:0005741), cytosol (GO:0005829), mitochondrion (GO:0005739)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Transcriptional Regulation by TP53	1
RNA Polymerase II Transcription	1
Generic Transcription Pathway	1
Gene expression (Transcription)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular response to stress	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
cytoplasm	2
autophagy of mitochondrion	1
macroautophagy	1
response to stress	1
organophosphate metabolic process	1
carbohydrate derivative metabolic process	1
phosphoglycerate kinase activity	1
phosphoglycerate mutase activity	1
phosphopyruvate hydratase activity	1
pyruvate kinase activity	1
pyruvate metabolic process	1
generation of precursor metabolites and energy	1
aerobic respiration	1
carbohydrate catabolic process	1
pyridine nucleotide catabolic process	1
glyceraldehyde-3-phosphate dehydrogenase [NAD(P)+] (phosphorylating) activity	1
ADP catabolic process	1
ATP metabolic process	1
nicotinamide nucleotide metabolic process	1
response to chemical	1
response to ionizing radiation	1
striated muscle cell apoptotic process	1
cardiac muscle cell apoptotic process	1
positive regulation of striated muscle cell apoptotic process	1
regulation of cardiac muscle cell apoptotic process	1
programmed cell death	1
regulation of programmed cell death	1
negative regulation of cellular process	1
pentose-phosphate shunt	1
regulation of generation of precursor metabolites and energy	1
regulation of carbohydrate catabolic process	1
regulation of NADP metabolic process	1
DNA repair	1
regulation of DNA repair	1
positive regulation of response to stimulus	1
positive regulation of DNA metabolic process	1
glycolytic process	1

Protein interactions and networks

STRING

2074 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TIGAR	PFKFB4	Q16877	956
TIGAR	HK2	P52789	904
TIGAR	SCO2	O43819	801
TIGAR	TP53	P04637	781
TIGAR	CYFIP2	Q96F07	764
TIGAR	PFKM	P08237	710
TIGAR	GLS2	Q9UI32	696
TIGAR	H6PD	O95479	665
TIGAR	G6PD	P11413	635
TIGAR	PFKFB3	Q16875	625
TIGAR	ATM	Q13315	599
TIGAR	PKM	P14618	598
TIGAR	PFKFB2	O60825	588
TIGAR	SLC2A1	P11166	585
TIGAR	LDHA	P00338	583

IntAct

58 interactions, top by confidence:

A	B	Type	Score
AKR7A3	AKR7A2	psi-mi:“MI:0914”(association)	0.890
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CASP6	TIGAR	psi-mi:“MI:0915”(physical association)	0.560
HIP1	TIGAR	psi-mi:“MI:0915”(physical association)	0.560
LAMP2	TIGAR	psi-mi:“MI:0915”(physical association)	0.560
SH3GLB1	TIGAR	psi-mi:“MI:0915”(physical association)	0.560
CTSG	MANBA	psi-mi:“MI:0914”(association)	0.530
TIGAR	HK2	psi-mi:“MI:0915”(physical association)	0.520
SBDS	DNM1L	psi-mi:“MI:0914”(association)	0.480
TWF1	TIGAR	psi-mi:“MI:0915”(physical association)	0.400
TIGAR	RPL11	psi-mi:“MI:0915”(physical association)	0.370
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
TWF1	ICAM1	psi-mi:“MI:0914”(association)	0.350
PNPLA4	ATP2B3	psi-mi:“MI:0914”(association)	0.350
GSX1	YKT6	psi-mi:“MI:0914”(association)	0.350
ALG8	ALDH1A1	psi-mi:“MI:0914”(association)	0.350
IGHG2	IGHG3	psi-mi:“MI:0914”(association)	0.350

BioGRID (70): PCBP1 (Co-fractionation), TKT (Co-fractionation), C12orf5 (Proximity Label-MS), C12orf5 (Affinity Capture-MS), C12orf5 (Affinity Capture-MS), C12orf5 (Affinity Capture-RNA), C12orf5 (Affinity Capture-MS), C12orf5 (Affinity Capture-MS), C12orf5 (Affinity Capture-Western), C12orf5 (Co-localization), C12orf5 (Co-localization), HK2 (Affinity Capture-Western), C12orf5 (Co-fractionation), C12orf5 (Co-fractionation), C12orf5 (Co-fractionation)

ESM2 similar proteins: A1A4L5, A3AZW5, A8Y5H7, B1WAX6, F4IBB2, O35552, O75417, P57075, Q07G10, Q0V9N0, Q0VC59, Q14527, Q16875, Q1JQA7, Q29RA5, Q2TBM9, Q3U213, Q3V3E1, Q4R4K2, Q4V7R0, Q5R9C1, Q6NMK6, Q6PC93, Q6PCN7, Q7ZVE3, Q80VJ4, Q80Y20, Q84MA1, Q8BGG7, Q8BZA9, Q8C0L9, Q8CGS6, Q8GY96, Q8L5Z4, Q8LPN3, Q8RX28, Q8TF42, Q8VYR2, Q92503, Q93WU4

Diamond homologs: A1AJW4, A1BE55, A1JJB8, A1R083, A1TC01, A1WDX2, A2SDN6, A4T096, A4TQH5, A4W6B3, A6LUA1, A6TI09, A6UEW3, A7FMF8, A7HZ35, A7MIJ0, A7ZVT7, A8A8C4, A8ALW1, A8G9J4, A9MR94, A9N7F5, A9R032, B0UBD4, B1GZZ1, B1IS24, B1JL20, B1LEK2, B1WAX6, B1XFK5, B1XS92, B2IEV6, B2K3K5, B2S101, B2TZS8, B2VH13, B3EFK8, B4EY52, B4T4I9, B4TH18

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
TIGAR	“down-regulates quantity”	“beta-D-fructofuranose 2,6-bisphosphate(4-)”	“chemical modification”
TP53	“up-regulates quantity by expression”	TIGAR	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 67 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.

GO biological processes:

GO term	Partners	Fold	FDR
endocytosis	7	11.1×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	20
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1070 predictions. Top by Δscore:

Variant	Effect	Δscore
12:4321300:GGCA:G	donor_gain	1.0000
12:4321301:GCA:G	donor_gain	1.0000
12:4321301:GCAG:G	donor_gain	1.0000
12:4321304:G:GG	donor_gain	1.0000
12:4321308:G:GG	donor_gain	1.0000
12:4323892:A:T	donor_gain	1.0000
12:4323896:G:GT	donor_gain	1.0000
12:4331278:A:AG	acceptor_gain	1.0000
12:4331278:AGT:A	acceptor_gain	1.0000
12:4331279:G:GA	acceptor_gain	1.0000
12:4331279:GTG:G	acceptor_gain	1.0000
12:4349817:A:AG	acceptor_gain	1.0000
12:4349818:G:GG	acceptor_gain	1.0000
12:4349818:GACC:G	acceptor_gain	1.0000
12:4349895:GG:G	donor_gain	1.0000
12:4349895:GGGTG:G	donor_loss	1.0000
12:4349896:GG:G	donor_gain	1.0000
12:4349897:G:GA	donor_loss	1.0000
12:4349898:T:TC	donor_loss	1.0000
12:4351261:TTTCA:T	acceptor_loss	1.0000
12:4351264:CA:C	acceptor_loss	1.0000
12:4351265:A:AG	acceptor_gain	1.0000
12:4351266:G:A	acceptor_loss	1.0000
12:4351266:G:GG	acceptor_gain	1.0000
12:4351266:GA:G	acceptor_gain	1.0000
12:4351266:GAA:G	acceptor_gain	1.0000
12:4351266:GAAAT:G	acceptor_gain	1.0000
12:4351374:CCAGG:C	donor_loss	1.0000
12:4351375:CAGG:C	donor_loss	1.0000
12:4351376:AGG:A	donor_loss	1.0000

AlphaMissense

1782 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:4352467:A:C	S197R	0.994
12:4352469:T:A	S197R	0.994
12:4352469:T:G	S197R	0.994
12:4337137:A:C	S57R	0.992
12:4337139:T:A	S57R	0.992
12:4337139:T:G	S57R	0.992
12:4337151:G:C	R61S	0.979
12:4337151:G:T	R61S	0.979
12:4352462:T:A	V195D	0.979
12:4349892:A:T	E89V	0.978
12:4352584:A:C	S236R	0.978
12:4352586:T:A	S236R	0.978
12:4352586:T:G	S236R	0.978
12:4337138:G:T	S57I	0.976
12:4337083:G:C	A39P	0.975
12:4351345:T:C	F117L	0.974
12:4351347:T:A	F117L	0.974
12:4351347:T:G	F117L	0.974
12:4349893:A:C	E89D	0.971
12:4349893:A:T	E89D	0.971
12:4321297:T:A	V9D	0.969
12:4337150:G:C	R61T	0.968
12:4352456:T:A	V193D	0.968
12:4331280:T:A	H11Q	0.967
12:4331280:T:G	H11Q	0.967
12:4331282:G:A	G12E	0.967
12:4349886:T:A	L87H	0.967
12:4349889:G:C	R88P	0.967
12:4337060:T:A	L31H	0.966
12:4321300:G:C	R10P	0.965

dbSNP variants (sampled 300 via entrez): RS1000015167 (12:4330761 G>A), RS1000062195 (12:4347395 T>C), RS1000132103 (12:4346305 T>A,C), RS1000163282 (12:4330396 A>G,T), RS1000201912 (12:4325678 G>A), RS1000304076 (12:4336711 G>A), RS1000400723 (12:4342894 C>T), RS1000412632 (12:4342201 A>G), RS1000493641 (12:4354397 GAGTTCTCTTTAACC>G), RS1000504690 (12:4325599 G>A), RS1000602476 (12:4337281 C>G,T), RS1000639402 (12:4320464 A>T), RS1000652048 (12:4325439 C>G), RS1000654864 (12:4337463 G>T), RS1000815658 (12:4351834 T>C)

Disease associations

OMIM: gene MIM:610775 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST000464_4	Acute lymphoblastic leukemia (childhood)	9.000000e-06
GCST001792_1	Colorectal cancer	3.000000e-08
GCST001792_2	Colorectal cancer	5.000000e-10
GCST001850_1	Major depressive disorder	9.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295958 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression	6
Aflatoxin B1	affects expression, increases expression	5
Cyclosporine	decreases expression, increases expression	4
sodium arsenite	increases expression, decreases expression, affects cotreatment, increases abundance	3
Cisplatin	increases expression	3
Tunicamycin	decreases expression, increases expression	3
bisphenol A	decreases expression, increases expression	2
Arsenic	affects cotreatment, increases abundance, increases expression, decreases expression	2
Doxorubicin	affects expression, increases expression	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Rotenone	decreases expression	2
Tobacco Smoke Pollution	increases expression, affects expression	2
Valproic Acid	affects expression, increases expression	2
Cadmium Chloride	increases abundance, increases expression	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
2,4,6-tribromophenol	increases expression	1
chloroacetaldehyde	increases expression	1
propionaldehyde	increases expression	1
sodium arsenate	decreases expression	1
decabromobiphenyl ether	increases expression	1
methoxyacetic acid	increases expression, affects cotreatment	1
arsenite	affects binding, increases reaction	1
potassium bromate	increases expression	1
tetrabromobisphenol A	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases 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
CHEMBL4118770	Binding	Binding affinity to TIGAR in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

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