GLI2

Summary

GLI2 (GLI family zinc finger 2, HGNC:4318) is a protein-coding gene on chromosome 2q14.2, encoding Zinc finger protein GLI2 (P10070). Functions as a transcription regulator in the hedgehog (Hh) pathway. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a protein which belongs to the C2H2-type zinc finger protein subclass of the Gli family. Members of this subclass are characterized as transcription factors which bind DNA through zinc finger motifs. These motifs contain conserved H-C links. Gli family zinc finger proteins are mediators of Sonic hedgehog (Shh) signaling and they are implicated as potent oncogenes in the embryonal carcinoma cell. The protein encoded by this gene localizes to the cytoplasm and activates patched Drosophila homolog (PTCH) gene expression. It is also thought to play a role during embryogenesis. The encoded protein is associated with several phenotypes- Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, preaxial polydactyly type IV, postaxial polydactyly types A1 and B.

Source: NCBI Gene 2736 — RefSeq curated summary.

At a glance

• Gene–disease (curated): postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 28
• Clinical variants (ClinVar): 1,308 total — 49 pathogenic, 44 likely-pathogenic
• Phenotypes (HPO): 192
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 207 downstream targets (CollecTRI)
• MANE Select transcript: NM_001374353

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4318
Approved symbol	GLI2
Name	GLI family zinc finger 2
Location	2q14.2
Locus type	gene with protein product
Status	Approved
Aliases	THP2, HPE9, THP1
Ensembl gene	ENSG00000074047
Ensembl biotype	protein_coding
OMIM	165230
Entrez	2736

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 8 protein_coding, 6 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000341310, ENST00000360874, ENST00000361492, ENST00000418323, ENST00000433812, ENST00000437950, ENST00000438299, ENST00000445186, ENST00000452319, ENST00000452692, ENST00000472722, ENST00000482119, ENST00000869361, ENST00000934404, ENST00000934405, ENST00000934406

RefSeq mRNA: 4 — MANE Select: NM_001374353 NM_001371271, NM_001374353, NM_001374354, NM_005270

CCDS: CCDS33283, CCDS92850

Canonical transcript exons

ENST00000361492 — 14 exons

Exon	Start	End
ENSE00001722873	120988208	120992653
ENSE00001731225	120735868	120736285
ENSE00003519169	120927361	120927466
ENSE00003548418	120968714	120968915
ENSE00003550380	120984471	120984743
ENSE00003575546	120951243	120951445
ENSE00003605001	120986278	120986614
ENSE00003615002	120955245	120955430
ENSE00003631799	120978434	120978583
ENSE00003631832	120797291	120797468
ENSE00003666873	120970393	120970606
ENSE00003688781	120982716	120982880
ENSE00003692751	120971941	120972063
ENSE00003902424	120974975	120975109

Expression profiles

Bgee: expression breadth ubiquitous, 211 present calls, max score 88.34.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.9267 / max 169.2776, expressed in 1019 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
22322	4.0552	911
22323	2.3587	757
22324	0.5129	365

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	88.34	gold quality
germinal epithelium of ovary	UBERON:0001304	84.85	gold quality
ventricular zone	UBERON:0003053	81.80	gold quality
saphenous vein	UBERON:0007318	81.01	gold quality
stromal cell of endometrium	CL:0002255	80.70	gold quality
ganglionic eminence	UBERON:0004023	80.40	gold quality
endothelial cell	CL:0000115	79.88	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	79.64	gold quality
right ovary	UBERON:0002118	78.10	gold quality
left ovary	UBERON:0002119	77.93	gold quality
vena cava	UBERON:0004087	77.12	gold quality
ovary	UBERON:0000992	76.87	gold quality
tendon of biceps brachii	UBERON:0008188	76.63	silver quality
pancreatic ductal cell	CL:0002079	76.25	silver quality
sural nerve	UBERON:0015488	75.48	gold quality
visceral pleura	UBERON:0002401	74.68	silver quality
trachea	UBERON:0003126	74.61	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.99	gold quality
mammary duct	UBERON:0001765	73.77	silver quality
pleura	UBERON:0000977	73.54	silver quality
parietal pleura	UBERON:0002400	73.52	gold quality
cardia of stomach	UBERON:0001162	72.68	gold quality
nipple	UBERON:0002030	72.51	gold quality
pericardium	UBERON:0002407	72.40	silver quality
superior surface of tongue	UBERON:0007371	72.15	gold quality
lateral globus pallidus	UBERON:0002476	71.91	silver quality
popliteal artery	UBERON:0002250	71.78	gold quality
body of uterus	UBERON:0009853	71.77	gold quality
tibial artery	UBERON:0007610	71.74	gold quality
trigeminal ganglion	UBERON:0001675	71.67	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.45

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

207 targets.

Target	Regulation
ABCA1	Repression
ACAT1
ADAM19
ADAM2
ADD3	Activation
AKAP4	Repression
AKR1C1
AP1	Unknown
ASCL1	Unknown
ATP10B	Repression
ATP4A
ATP9A	Repression
B3GNT9
BCL2	Activation
BCL6	Repression
BDKRB2
BGLAP	Activation
BHLHE41	Unknown
BLVRA	Repression
BMP1	Repression
BMP2	Activation
BMP4	Activation
BMP7	Repression
BRD2	Activation
CAMK1	Activation
CCL17	Activation
CCND1	Activation
CCND2	Activation
CCNG2	Repression
CD2

JASPAR motifs

Motif	Name	Family
MA0734.1	GLI2	More than 3 adjacent zinc fingers
MA0734.2	GLI2	More than 3 adjacent zinc fingers

JASPAR matrix evidence (PMIDs): PMID:2105456

Upstream regulators (CollecTRI, top): CTNNB1, CTNNBIP1, CXCL1, FOXA2, MEOX1, RXRG, SMAD3, SOX2, SOX9, TCF7L2, TP53

miRNA regulators (miRDB)

101 targeting GLI2, 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-6867-5P	100.00	82.21	3464
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-3605-5P	99.96	67.12	932
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-12119	99.87	68.35	1653
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-5003-3P	99.85	69.29	2517

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• GLI2 has a role in defective anterior pituitary formation and pan-hypopituitarism, and in human head development (PMID:14581620)
• GLI2 expression in human keratinocytes results in a marked downregulation of epidermal differentiation markers. (PMID:14691458)
• important role for GLI2 in regulating epidermal proliferation and skin tumorigenesis. (PMID:15175043)
• Our results establish the presence of an amino-terminal transcriptional repressor domain that plays a critical role in modulating the function of wild-type GLI2 and is essential for dominant-negative activity of a GLI2 mutant associated with human disease (PMID:15994174)
• Higher levels of TPH2 mRNA were found throughout the entire extent of the rostrocaudal axis of the median raphe nuclei in major depression and suicide. (PMID:16192985)
• Upregulation of largely overlapping sets of target genes was effected by both factors,GLI1 and GLI2, repression occurred predominantly in response to GLI2. (PMID:16434164)
• Alternative splicing may be another important regulatory mechanism for the modulation of repressor and activator properties of GLI2 protein. (PMID:16553965)
• beta-TrCP2 is a pivotal regulator of Gli2 expression and there may be an important role for posttranslational modulation of GLI2 protein levels in Hh pathway-associated human prostate cancer (PMID:16651270)
• transforming growth factor-beta has a role in Smad3-dependent activation of Gli2 and Gli1 expression (PMID:17638910)
• GLI2 plays a critical role in the malignant phenotype of prostate cancer cells (PMID:18006803)
• Since Gli2 silencing not only downregulates cFlip, but also Bcl-2, Gli2 could be a key target for a novel therapeutic approach in basal cell carcinoma. (PMID:18264131)
• These results reveal a key role of GLI2 in activation of the activin/BMP antagonist FST in response to hedgehog (HH) signaling. (PMID:18319260)
• increased levels of GLI2 correlates with AI progression (PMID:18794086)
• The stroma, in a tissue-specific manner, determines whether certain GLI2 oncogenic traits are expressed. (PMID:19015636)
• Gli-2 rather than Gli-1 may play a pivotal role in Hedgehog signaling of endometrial carcinoma. (PMID:19432668)
• Sonic hedgehog protein, GLI1-3 and ATP-binding cassette G2 are aberrantly expressed in diffuse large B-cell lymphoma. (PMID:19593328)
• Data suggest a novel mechanism in which PKA down-regulates Hedgehog signaling by promoting the interaction between 14-3-3 and Gli as well as proteolysis. (PMID:19996099)
• Constitutive expression of the human hGli2 Delta N in porcine keratinocytes causes cutaneous changes not seen in the murine model. A multiple species animal model approach is needed to understand the role of Gli2 in mammalian skin. (PMID:20099029)
• Expression of SHH, GLI family zinc finger 2 (GLI2) and BMP4 mRNA and protein in the posterior wall of the terminal rectum in 40 patients with orectal malformations, were assessed. (PMID:20146882)
• The finding that Gli2 co-immunoprecipitates with androgen receptor protein suggests that an interaction between these proteins might be the basis for Hedgehog/Gli support of androgen signaling (PMID:20420697)
• The invasiveness of human bladder TCC lines strongly correlated with expression of Gli2, a downstream mediator of Hh signaling. (PMID:20488474)
• In human melanoma cells, GLI2 expression was heterogeneous, associated with loss of E-cadherin and increased in the most aggressive tumors. In this preclinical study, GLI2 was directly involved in driving melanoma invasion and metastasis. (PMID:20660365)
• These phenotypes support partial penetrance, variable polydactyly, midline facial defects, and pituitary hormone deficiencies, including diabetes insipidus, conferred by heterozygous frameshift or nonsense GLI2 mutations. (PMID:20685856)
• In human hepatocellular, the hedgehog signaling pathway is involved in the differentiation and proliferation of tumor cells, in part through inducing nuclear accumulation of Gli2 protein and subsequent upregulation of FoxM1 protein. (PMID:20712011)
• our findings support a possible contribution of GLI2 to tardive dyskinesia susceptibility. (PMID:20939080)
• A fragment of the Hh-responsive GLI2 transcription factor directly binds and inhibits the p16 promoter and senescence is associated with the loss of nuclear GLI2. (PMID:21095584)
• Novel sequence variants were found in the GLI2 gene in patients with marked involvement of the temporomandibular joint, a new clinical finding observed with mutations of this gene. (PMID:21204792)
• CCL5 signaling induces GLI2 through a PI3K-AKT-IkappaBalpha-p65 pathway and requires GLI2 transcriptional activity to modulate IL-6 expression and Ig secretion in vitro and in vivo (PMID:21454528)
• data suggest that Gli2 plays a predominant role in the proliferation and apoptosis resistance of HCC cells, and that knockdown of Gli2 may be a novel anticancer strategy for the treatment of HCC (PMID:21695716)
• These findings thus identify GLI2 as a critical transcription factor antagonizing M-MITF function to promote melanoma cell phenotypic plasticity and invasive behavior. (PMID:21801332)
• This short review summarizes recent knowledge about GLI2 function and mechanisms of action downstream of TGF-beta in cancer.[Review] (PMID:21862631)
• Gli1 and Gli2 are highly expressed in in non-Hodgkin’s lymphoma. Expression positively correlated to clinical staging of NHL. (PMID:22040957)
• Gli2 expression in HL60 and U937 cells induced by TGF-beta is Smad3-dependent and independent of Hh receptor signaling. (PMID:22395235)
• identified a GLI2 binding site within the -334/-296 region of the M-MITF promoter, critical for GLI2-driven transcriptional repression (PMID:22496449)
• The immunoexpression of Shh, Smo and Gli2 proteins was lower in Helicobacter pylori-positive group compared to Helicobacter pylori-negative group (PMID:22535603)
• Transcriptional regulation of TGF-beta1 by GLI2 is a new extension to Sonic Hedgehog and TGF-beta1 cross-regulation. (PMID:22859956)
• We genotyped the SLC6A4 5-HTTLPR (rs4795541, rs25531) and TPH2 1125A>T (rs4290270) variants and evaluated their role in moderating disulfiram treatment for cocaine dependence. (PMID:22925276)
• A relatively high frequency of non-synonymous GLI2 variants was identified in patients with congenital growth hormone deficiency and combined pituitary hormone deficiency without other brain defects. (PMID:22967285)
• Overexpression of MAP3K10 resulted in upregulation of Gli-1 and Gli-2 in pancreatic ductal adenocarcinoma cells. (PMID:23178452)
• THE MEK-RSK cascade positively regulates GLI2 stabilization and represses its degradation via inhibiting GSK-3beta-dependent phosphorylation and ubiquitination of GLI2. (PMID:23208494)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gli2b	ENSDARG00000020884
danio_rerio	gli2a	ENSDARG00000025641
mus_musculus	Gli2	ENSMUSG00000048402

Paralogs (14): ZIC2 (ENSG00000043355), ZXDC (ENSG00000070476), GLI3 (ENSG00000106571), GLIS3 (ENSG00000107249), GLI1 (ENSG00000111087), GLIS2 (ENSG00000126603), AEBP2 (ENSG00000139154), ZIC5 (ENSG00000139800), ZIC1 (ENSG00000152977), ZIC3 (ENSG00000156925), GLIS1 (ENSG00000174332), ZIC4 (ENSG00000174963), ZXDA (ENSG00000198205), ZXDB (ENSG00000198455)

Protein

Protein identifiers

Zinc finger protein GLI2 — P10070 (reviewed: P10070)

Alternative names: GLI family zinc finger protein 2, Tax helper protein

All UniProt accessions (6): P10070, A0A6Q8PH00, A0A7I2PJA1, F2Z2B4, H7C1U2, Q1PSW9

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a transcription regulator in the hedgehog (Hh) pathway. Functions as a transcriptional activator. May also function as transcriptional repressor. Requires STK36 for full transcriptional activator activity. Required for normal embryonic development. Involved in the smoothened (SHH) signaling pathway. Involved in the smoothened (SHH) signaling pathway. Involved in the smoothened (SHH) signaling pathway. Involved in the smoothened (SHH) signaling pathway. Acts as a transcriptional activator in T-cell leukemia virus type 1 (HTLV-1)-infected cells in a Tax-dependent manner. Binds to the DNA sequence 5’-GAACCACCCA-3’ which is part of the Tax-responsive element (TRE-2S) regulatory element that augments the Tax-dependent enhancer of HTLV-1. (Microbial infection) Acts as a transcriptional activators in T-cell leukemia virus type 1 (HTLV-1)-infected cells in a Tax-dependent manner. Binds to the DNA sequence 5’-GAACCACCCA-3’ which is part of the Tax-responsive element (TRE-2S) regulatory element that augments the Tax-dependent enhancer of HTLV-1. (Microbial infection) Acts as a transcriptional activators in T-cell leukemia virus type 1 (HTLV-1)-infected cells in a Tax-dependent manner. Binds to the DNA sequence 5’-GAACCACCCA-3’ which is part of the Tax-responsive element (TRE-2S) regulatory element that augments the Tax-dependent enhancer of HTLV-1. (Microbial infection) Acts as a transcriptional activators in T-cell leukemia virus type 1 (HTLV-1)-infected cells in a Tax-dependent manner. Binds to the DNA sequence 5’-GAACCACCCA-3’ which is part of the Tax-responsive element (TRE-2S) regulatory element that augments the Tax-dependent enhancer of HTLV-1. Acts as a transcriptional repressor.

Subunit / interactions. Interaction with ZIC1 and ZIC2. Interacts with STK36. Interacts with SUFU; this inhibits transcriptional activation mediated by GLI2. Interacts (via C-terminal internal region) with FOXC1 (via N-terminus); this interaction is direct and increases GLI2 DNA-binding and transcriptional activity through a smoothened (SMO)-independent Hedgehog (Hh) signaling pathway. Interacts with TMEM216; this interaction promotes nuclear localization of GLI2.

Subcellular location. Nucleus. Cytoplasm. Cell projection. Cilium Nucleus Nucleus.

Tissue specificity. Expressed in breast cancers (at protein level). Isoform 1 and isoform 4 are expressed in HTLV-1-infected T-cell lines (at protein level). Isoform 1 and isoform 2 are strongly expressed in HTLV-1-infected T-cell lines. Isoform 3 and isoform 4 are weakly expressed in HTLV-1-infected T-cell lines.

Post-translational modifications. Phosphorylated in vitro by ULK3. Phosphorylated by DYRK2; this inhibits GLI2 transcription factor activity and promotes proteasomal degradation of GLI2. Acetylation at Lys-757 inhibits Hh target gene expression, probably by impeding entry into chromatin thus preventing promoter occupancy.

Disease relevance. Holoprosencephaly 9 (HPE9) [MIM:610829] A form of holoprosencephaly, a structural anomaly of the brain in which the developing forebrain fails to correctly separate into right and left hemispheres. It is a genetically and clinically heterogeneous disorder with a wide spectrum of severity, ranging from alobar holoprosencephaly with severe facial abnormalities, such as cyclopia and proboscis, to mild forms that include lobar or microform holoprosencephaly, without cerebral malformations and with mild craniofacial defects. HPE9 is characterized by defective anterior pituitary formation and pan-hypopituitarism, with or without overt forebrain cleavage abnormalities, and holoprosencephaly-like midfacial hypoplasia. HPE9 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry. Culler-Jones syndrome (CJS) [MIM:615849] An autosomal dominant disorder with incomplete penetrance and variable expressivity, characterized by pituitary abnormalities including ectopic or non-visible posterior pituitary lobe, growth hormone deficiency, combined pituitary hormone deficiency, and, in some patients, additional features such as postaxial polydactyly, midline facial defects, and developmental delay. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The N-terminal domain confers transcriptional repressor activity, while the C-terminal domain mediates transcriptional activation.

Similarity. Belongs to the GLI C2H2-type zinc-finger protein family.

Isoforms (5)

UniProt ID	Names	Canonical?
P10070-5	5, GLI2	yes
P10070-1	1, Alpha, GLI2star, GLI2deltaN
P10070-2	2, Beta
P10070-3	3, Gamma
P10070-4	4, Delta

RefSeq proteins (4): NP_001358200, NP_001361282, NP_001361283, NP_005261 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013087	Znf_C2H2_type	Domain
IPR036236	Znf_C2H2_sf	Homologous_superfamily
IPR043359	GLI-like	Family
IPR056436	Znf-C2H2_ZIC1-5/GLI1-3-like	Domain

Pfam: PF00096, PF23561

UniProt features (57 total): sequence variant 15, region of interest 9, compositionally biased region 9, modified residue 8, zinc finger region 5, splice variant 4, sequence conflict 4, cross-link 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P10070-F1	42.68	0.01

Functional residue map

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

Post-translational modifications (10): 149, 234, 236, 242, 388, 725, 757, 1011, 50, 50

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-5610783	Degradation of GLI2 by the proteasome
R-HSA-5610787	Hedgehog ‘off’ state
R-HSA-5632684	Hedgehog ‘on’ state
R-HSA-5635851	GLI proteins bind promoters of Hh responsive genes to promote transcription
R-HSA-8941284	RUNX2 regulates chondrocyte maturation

MSigDB gene sets: 613 (showing top): GOBP_SPINAL_CORD_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_DNA_REPLICATION, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, BROWNE_HCMV_INFECTION_6HR_DN, GOBP_METENCEPHALON_DEVELOPMENT, GOBP_CELLULAR_RESPONSE_TO_VIRUS, GOBP_EPIDERMIS_MORPHOGENESIS, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, KEGG_HEDGEHOG_SIGNALING_PATHWAY, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN

GO Biological Process (73): negative regulation of transcription by RNA polymerase II (GO:0000122), skeletal system development (GO:0001501), osteoblast differentiation (GO:0001649), kidney development (GO:0001822), osteoblast development (GO:0002076), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), smoothened signaling pathway (GO:0007224), pattern specification process (GO:0007389), axon guidance (GO:0007411), ventral midline development (GO:0007418), hindgut morphogenesis (GO:0007442), heart development (GO:0007507), epidermal cell differentiation (GO:0009913), proximal/distal pattern formation (GO:0009954), floor plate formation (GO:0021508), spinal cord dorsal/ventral patterning (GO:0021513), ventral spinal cord development (GO:0021517), cerebellar cortex morphogenesis (GO:0021696), spinal cord ventral commissure morphogenesis (GO:0021965), pituitary gland development (GO:0021983), lung development (GO:0030324), mammary gland development (GO:0030879), hindbrain development (GO:0030902), hair follicle morphogenesis (GO:0031069), positive regulation of T cell differentiation in thymus (GO:0033089), tube development (GO:0035295), odontogenesis of dentin-containing tooth (GO:0042475), positive regulation of DNA replication (GO:0045740), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), embryonic digestive tract development (GO:0048566), developmental growth (GO:0048589), neuron development (GO:0048666), branching morphogenesis of an epithelial tube (GO:0048754), cellular response to virus (GO:0098586), in utero embryonic development (GO:0001701), morphogenesis of an epithelium (GO:0002009), chondrocyte differentiation (GO:0002062), cell population proliferation (GO:0008283)

GO Molecular Function (16): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription factor activity (GO:0003700), zinc ion binding (GO:0008270), sequence-specific DNA binding (GO:0043565), sequence-specific double-stranded DNA binding (GO:1990837), promoter-specific chromatin binding (GO:1990841), transcription cis-regulatory region binding (GO:0000976), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), chromatin binding (GO:0003682), double-stranded DNA binding (GO:0003690), protein binding (GO:0005515), chromatin DNA binding (GO:0031490), metal ion binding (GO:0046872)

GO Cellular Component (16): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), centrosome (GO:0005813), cytosol (GO:0005829), cilium (GO:0005929), ciliary basal body (GO:0036064), ciliary tip (GO:0097542), ciliary base (GO:0097546), GLI-SUFU complex (GO:1990788), cytoplasm (GO:0005737), axoneme (GO:0005930), membrane (GO:0016020), nuclear speck (GO:0016607), motile cilium (GO:0031514), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Signaling by Hedgehog	2
Hedgehog ‘off’ state	1
Hedgehog ‘on’ state	1
RUNX2 regulates bone development	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	8
cilium	4
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
DNA binding	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
animal organ development	2
regulation of DNA-templated transcription	2
anatomical structure development	2
anatomical structure morphogenesis	2
spinal cord development	2
transcription cis-regulatory region binding	2
chromatin binding	2
binding	2
nuclear lumen	2
microtubule organizing center	2
negative regulation of DNA-templated transcription	1
system development	1
ossification	1
cell differentiation	1
renal system development	1
osteoblast differentiation	1
cell development	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cell surface receptor signaling pathway	1
multicellular organism development	1
multicellular organismal process	1
axonogenesis	1
neuron projection guidance	1
central nervous system development	1
digestive tract morphogenesis	1
hindgut development	1
circulatory system development	1
epidermis development	1
epithelial cell differentiation	1
regionalization	1
ventral midline development	1
floor plate morphogenesis	1

Protein interactions and networks

STRING

3010 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GLI2	SUFU	Q9UMX1	999
GLI2	THOC2	Q8NI27	992
GLI2	CYLD	Q9NQC7	988
GLI2	THOC3	Q96J01	986
GLI2	SHH	Q15465	973
GLI2	PTCH1	Q13635	967
GLI2	THOC1	Q96FV9	960
GLI2	SMO	Q99835	954
GLI2	KIF7	Q2M1P5	936
GLI2	RUNX2	Q13950	862
GLI2	RAB23	Q9ULC3	853
GLI2	IHH	Q14623	834
GLI2	HHIP	Q96QV1	820
GLI2	DHH	O43323	807
GLI2	PTCH2	Q9Y6C5	796

IntAct

21 interactions, top by confidence:

A	B	Type	Score
GLI2	BTRC	psi-mi:“MI:0915”(physical association)	0.580
GLI2	KIF7	psi-mi:“MI:0914”(association)	0.570
GLI2	SMAD3	psi-mi:“MI:0914”(association)	0.560
GLI2	SMAD3	psi-mi:“MI:0915”(physical association)	0.560
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
PNMA2	CCDC85C	psi-mi:“MI:0914”(association)	0.530
TSG101	GLI2	psi-mi:“MI:0407”(direct interaction)	0.440
GLI2	YWHAZ	psi-mi:“MI:0914”(association)	0.350
EGLN3	FAM168B	psi-mi:“MI:0914”(association)	0.350
GLI2	SPOP	psi-mi:“MI:0914”(association)	0.350
CPNE2	SUPT5H	psi-mi:“MI:0914”(association)	0.350
HSPA8	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
MLH1	GLI2	psi-mi:“MI:0914”(association)	0.350
PPP2R2B	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
GLI2	CNOT1	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (81): SPOP (Affinity Capture-Western), GLI2 (Affinity Capture-Western), USP7 (Affinity Capture-Western), Sufu (Affinity Capture-Western), GLI2 (Affinity Capture-MS), GLI2 (Affinity Capture-Western), CUL3 (Affinity Capture-Western), GLI2 (Affinity Capture-Western), GLI2 (Affinity Capture-Western), SPOP (Affinity Capture-Western), GLI2 (Affinity Capture-RNA), GLI2 (Affinity Capture-MS), GLI2 (Two-hybrid), GLI2 (Affinity Capture-MS), GLI2 (Reconstituted Complex)

ESM2 similar proteins: A0JC51, A5ABV9, O08656, O09100, O18896, O57311, O60481, O73689, O95409, P09022, P10070, P19544, P22561, P23769, P23770, P23771, P23772, P23824, P25932, P46684, P49639, P49952, P54655, P55878, P70062, P70063, Q08DV0, Q0VGT2, Q15915, Q62520, Q62521, Q6DJQ6, Q6VVD7, Q6XP49, Q7TQ40, Q800Q5, Q8JJC0, Q91689, Q924A0, Q924Y4

Diamond homologs: A0A5K4F1D0, A0JC51, A4FV57, O57311, O60481, O73689, O95409, P08151, P10070, P10071, P19538, P34708, P39768, P46684, P47806, P55878, P55879, Q0VGT2, Q15915, Q17308, Q5IS56, Q61467, Q61602, Q62520, Q62521, Q6DJQ6, Q6GR30, Q6XP49, Q6ZN18, Q7JNM3, Q7K0S9, Q7SXV2, Q7TQ40, Q8JJC0, Q8K1M4, Q8N9L1, Q8NBF1, Q8NEA6, Q8SV95, Q8VDL9

SIGNOR signaling

35 interactions.

A	Effect	B	Mechanism
CSNK1A1L	up-regulates	GLI2	phosphorylation
CSNK1A1	down-regulates	GLI2	phosphorylation
GLI2	“up-regulates quantity by expression”	BMP2	“transcriptional regulation”
SHH	“up-regulates activity”	GLI2
CXCL1	“up-regulates quantity by expression”	GLI2	“transcriptional regulation”
GSK3B	“down-regulates quantity by destabilization”	GLI2	phosphorylation
PRKACA	down-regulates	GLI2	phosphorylation
2-[[3-[[2-(dimethylamino)phenyl]methyl]-2-pyridin-4-yl-1,3-diazinan-1-yl]methyl]-N,N-dimethylaniline	down-regulates	GLI2	“chemical inhibition”
PRKACA	“down-regulates quantity by destabilization”	GLI2	phosphorylation
4-(2,4,5-tripyridin-4-yl-3-thiophenyl)pyridine	down-regulates	GLI2	“chemical inhibition”
KIF7	“up-regulates quantity by stabilization”	GLI2	binding
GLI2	“up-regulates quantity by expression”	FOXF1	“transcriptional regulation”
GLI2	“up-regulates quantity by expression”	IFITM5	“transcriptional regulation”
ULK3	“up-regulates activity”	GLI2	phosphorylation
SPOP	“down-regulates quantity”	GLI2	ubiquitination
SUFU	“up-regulates quantity by stabilization”	GLI2	binding
GLI2	“form complex”	GLI1/GLI2	binding
GLI2	“up-regulates quantity”	OLIG2	“transcriptional regulation”
DYRK2	“down-regulates quantity by destabilization”	GLI2	phosphorylation
SUFU	“down-regulates activity”	GLI2	relocalization
BTRC	“down-regulates quantity by destabilization”	GLI2	ubiquitination
GLI2	“up-regulates quantity by expression”	GLI1	“transcriptional regulation”
GLI2	“up-regulates quantity by expression”	PTCH1	“transcriptional regulation”
GLI2	“up-regulates quantity by expression”	HHIP	“transcriptional regulation”
SOX17	up-regulates	GLI2

Disease & clinical

Clinical variants and AI predictions

ClinVar

1308 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	49
Likely pathogenic	44
Uncertain significance	689
Likely benign	318
Benign	78

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1077120	NM_001374353.1(GLI2):c.2338del (p.Thr780fs)	Pathogenic
1285585	NM_001374353.1(GLI2):c.2283del (p.Ala763fs)	Pathogenic
1319873	NM_001374353.1(GLI2):c.457+1G>A	Pathogenic
1335397	NM_001374353.1(GLI2):c.2286del (p.Ala763fs)	Pathogenic
1343182	NM_001374353.1(GLI2):c.1905+1G>T	Pathogenic
1371947	NM_001374353.1(GLI2):c.49del (p.Ser17fs)	Pathogenic
13834	GLI2, 1-BP DEL, NT2274	Pathogenic
13835	NM_001374353.1(GLI2):c.1272G>A (p.Trp424Ter)	Pathogenic
13836	NM_001374353.1(GLI2):c.1384C>G (p.Arg462Gly)	Pathogenic
139428	GLI2, 1256TER	Pathogenic
139429	NM_001374353.1(GLI2):c.2311_2317del (p.Leu771fs)	Pathogenic
139430	NM_001374353.1(GLI2):c.2030_2033del (p.Leu677fs)	Pathogenic
139431	NM_001374353.1(GLI2):c.1138G>T (p.Glu380Ter)	Pathogenic
2006699	NM_001374353.1(GLI2):c.4311C>G (p.Tyr1437Ter)	Pathogenic
2034980	NM_001374353.1(GLI2):c.1393A>T (p.Lys465Ter)	Pathogenic
2112984	NM_001374353.1(GLI2):c.9dup (p.Ser4fs)	Pathogenic
225098	NM_001374353.1(GLI2):c.562del (p.Ala188fs)	Pathogenic
2265770	NM_001374353.1(GLI2):c.1718del (p.Gly573fs)	Pathogenic
235076	NM_001374353.1(GLI2):c.790C>T (p.Arg264Ter)	Pathogenic
2429354	NM_001374353.1(GLI2):c.2302_2306dup (p.Arg770fs)	Pathogenic
2441742	NM_001374353.1(GLI2):c.2454del (p.Ser819fs)	Pathogenic
2582463	NM_001374353.1(GLI2):c.2509_2510del (p.Ser837fs)	Pathogenic
2628336	NM_001374353.1(GLI2):c.3523C>T (p.Gln1175Ter)	Pathogenic
2631388	NM_001374353.1(GLI2):c.798_804del (p.Ser266fs)	Pathogenic
2932634	NM_001374353.1(GLI2):c.1934C>A (p.Ser645Ter)	Pathogenic
2951021	NM_001374353.1(GLI2):c.2651del (p.Pro884fs)	Pathogenic
3375304	NM_001374353.1(GLI2):c.3590dup (p.Ile1199fs)	Pathogenic
3389327	NM_001374353.1(GLI2):c.1408C>T (p.Gln470Ter)	Pathogenic
37082	NM_001374353.1(GLI2):c.864_865del (p.His289fs)	Pathogenic
374313	NM_001374353.1(GLI2):c.3210dup (p.Thr1071fs)	Pathogenic

SpliceAI

4686 predictions. Top by Δscore:

Variant	Effect	Δscore
2:120797286:TTTA:T	acceptor_loss	1.0000
2:120797287:TTAG:T	acceptor_loss	1.0000
2:120797289:A:AG	acceptor_gain	1.0000
2:120797289:AG:A	acceptor_gain	1.0000
2:120797290:G:GG	acceptor_gain	1.0000
2:120797290:GG:G	acceptor_gain	1.0000
2:120797290:GGAT:G	acceptor_gain	1.0000
2:120797290:GGATT:G	acceptor_gain	1.0000
2:120797465:GGAG:G	donor_gain	1.0000
2:120797466:G:GT	donor_gain	1.0000
2:120797466:G:T	donor_gain	1.0000
2:120797467:AG:A	donor_loss	1.0000
2:120797468:GG:G	donor_loss	1.0000
2:120797469:G:A	donor_loss	1.0000
2:120797470:T:A	donor_loss	1.0000
2:120927359:A:AG	acceptor_gain	1.0000
2:120927360:G:GG	acceptor_gain	1.0000
2:120927360:GT:G	acceptor_gain	1.0000
2:120927465:GG:G	donor_gain	1.0000
2:120927466:GG:G	donor_gain	1.0000
2:120953653:G:GT	donor_gain	1.0000
2:120955236:T:TA	acceptor_gain	1.0000
2:120955240:CACA:C	acceptor_loss	1.0000
2:120955241:ACAGT:A	acceptor_gain	1.0000
2:120955243:A:AG	acceptor_gain	1.0000
2:120955243:AGT:A	acceptor_gain	1.0000
2:120955243:AGTG:A	acceptor_gain	1.0000
2:120955244:G:GA	acceptor_gain	1.0000
2:120955244:GT:G	acceptor_gain	1.0000
2:120955244:GTG:G	acceptor_gain	1.0000

AlphaMissense

10353 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:120975056:T:C	C439R	1.000
2:120978473:T:C	F470L	1.000
2:120978475:T:A	F470L	1.000
2:120978475:T:G	F470L	1.000
2:120978479:T:A	C472S	1.000
2:120978479:T:C	C472R	1.000
2:120978480:G:A	C472Y	1.000
2:120978480:G:C	C472S	1.000
2:120978481:C:G	C472W	1.000
2:120978485:T:A	W474R	1.000
2:120978485:T:C	W474R	1.000
2:120978487:G:C	W474C	1.000
2:120978487:G:T	W474C	1.000
2:120978494:T:A	C477S	1.000
2:120978494:T:C	C477R	1.000
2:120978495:G:A	C477Y	1.000
2:120978495:G:C	C477S	1.000
2:120978496:C:G	C477W	1.000
2:120978515:T:C	F484L	1.000
2:120978516:T:C	F484S	1.000
2:120978517:C:A	F484L	1.000
2:120978517:C:G	F484L	1.000
2:120978534:T:C	L490P	1.000
2:120978542:C:A	H493N	1.000
2:120978542:C:G	H493D	1.000
2:120978543:A:G	H493R	1.000
2:120978544:C:A	H493Q	1.000
2:120978544:C:G	H493Q	1.000
2:120978549:G:C	R495P	1.000
2:120978552:G:C	R496P	1.000

dbSNP variants (sampled 300 via entrez): RS1000002447 (2:120961902 T>G), RS1000016114 (2:120788057 G>A,C), RS1000027037 (2:120770077 T>A), RS1000033869 (2:120962064 A>G), RS1000035668 (2:120777381 G>A,C,T), RS1000047435 (2:120852389 T>C), RS1000058374 (2:120896637 A>G), RS1000085389 (2:120775319 A>G), RS1000086325 (2:120886879 A>G), RS1000086412 (2:120920271 C>T), RS1000090289 (2:120927739 C>T), RS1000116291 (2:120991652 A>G), RS1000122858 (2:120905936 C>A,G), RS1000125402 (2:120807851 C>A,G), RS1000136649 (2:120734601 A>T)

Disease associations

OMIM: gene MIM:165230 | disease phenotypes: MIM:610829, MIM:615849, MIM:210400, MIM:123100, MIM:209900, MIM:236100, MIM:277590, MIM:307300, MIM:312100, MIM:312300, MIM:613038, MIM:615419, MIM:108010, MIM:616364

GenCC curated gene-disease

Disease	Classification	Inheritance
holoprosencephaly 9	Definitive	Autosomal dominant
postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome	Definitive	Autosomal dominant
holoprosencephaly	Supportive	Autosomal recessive
combined pituitary hormone deficiencies, genetic form	Supportive	Autosomal dominant

Mondo (25): holoprosencephaly 9 (MONDO:0012563), postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome (MONDO:0014369), corpus callosum lipoma (MONDO:0003845), skin tag (MONDO:0004026), bifid nose, autosomal recessive (MONDO:0008866), facial cleft (MONDO:0015411), coloboma of superior eyelid (MONDO:0015480), benign neoplasm of eye (MONDO:0021454), disorder of sexual differentiation (MONDO:0002145), craniosynostosis (MONDO:0015469), Bardet-Biedl syndrome (MONDO:0015229), microform holoprosencephaly (MONDO:0017219), pituitary stalk interruption syndrome (MONDO:0019828), holoprosencephaly 1 (MONDO:0009349), intellectual disability (MONDO:0001071)

Orphanet (20): Holoprosencephaly (Orphanet:2162), Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome (Orphanet:420584), Facial cleft (Orphanet:141229), Coloboma of superior eyelid (Orphanet:155884), Bifid nose (Orphanet:2695), Difference of sex development (Orphanet:90771), Craniosynostosis (Orphanet:1531), Male infertility with azoospermia or oligozoospermia due to single gene mutation (Orphanet:399805), Bardet-Biedl syndrome (Orphanet:110), Microphthalmia-anophthalmia-coloboma (Orphanet:98555), Microform holoprosencephaly (Orphanet:280200), Pituitary stalk interruption syndrome (Orphanet:95496), Weaver syndrome (Orphanet:3447), Partial androgen insensitivity syndrome (Orphanet:90797), Combined pituitary hormone deficiencies, genetic forms (Orphanet:95494)

HPO phenotypes

192 total (30 of 192 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000054	Micropenis
HP:0000062	Ambiguous genitalia
HP:0000104	Renal agenesis
HP:0000119	Abnormality of the genitourinary system
HP:0000135	Hypogonadism
HP:0000141	Amenorrhea
HP:0000161	Median cleft upper lip
HP:0000175	Cleft palate
HP:0000179	Thick lower lip vermilion
HP:0000193	Bifid uvula
HP:0000202	Orofacial cleft
HP:0000204	Cleft upper lip
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000260	Wide anterior fontanel
HP:0000272	Malar flattening
HP:0000286	Epicanthus
HP:0000322	Short philtrum
HP:0000324	Facial asymmetry
HP:0000327	Hypoplasia of the maxilla
HP:0000358	Posteriorly rotated ears
HP:0000384	Preauricular skin tag
HP:0000395	Prominent antihelix
HP:0000400	Macrotia
HP:0000407	Sensorineural hearing impairment

GWAS associations

28 associations (top):

Study	Trait	p-value
GCST000824_7	Erectile dysfunction and prostate cancer treatment	5.000000e-06
GCST001585_19	Breast size	3.000000e-11
GCST001814_12	Age-related macular degeneration	7.000000e-06
GCST001814_24	Age-related macular degeneration	5.000000e-07
GCST002702_31	Height	6.000000e-08
GCST002875_13	Diisocyanate-induced asthma	4.000000e-06
GCST003372_43	Glomerular filtration rate (creatinine)	1.000000e-07
GCST006627_68	Diastolic blood pressure	2.000000e-09
GCST006867_14	Type 2 diabetes	3.000000e-11
GCST007234_7	Acne (severe)	4.000000e-08
GCST007495_1	Estimated glomerular filtration rate in coronary artery disease and impaired kidney function	2.000000e-06
GCST007733_9	Serum uric acid levels	1.000000e-09
GCST007876_100	Estimated glomerular filtration rate	2.000000e-08
GCST008163_166	Height	9.000000e-08
GCST008163_367	Height	2.000000e-09
GCST008163_429	Height	3.000000e-06
GCST008163_573	Height	2.000000e-06
GCST008839_120	Height	4.000000e-11
GCST008839_368	Height	6.000000e-19
GCST009379_234	Type 2 diabetes	8.000000e-06
GCST009379_235	Type 2 diabetes	4.000000e-09
GCST009379_236	Type 2 diabetes	3.000000e-06
GCST012053_4	Weight	7.000000e-09
GCST012226_188	Waist circumference adjusted for body mass index	2.000000e-10
GCST012490_526	Femur bone mineral density x serum urate levels interaction	8.000000e-09
GCST90000025_816	Appendicular lean mass	2.000000e-13
GCST90011900_131	Serum alkaline phosphatase levels	4.000000e-13
GCST90020029_515	Waist circumference adjusted for body mass index	4.000000e-08

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0006995	response to diisocyanate
EFO:0006336	diastolic blood pressure
EFO:0004761	uric acid measurement
EFO:0004338	body weight
EFO:0007789	BMI-adjusted waist circumference
EFO:0004531	urate measurement
EFO:0004980	appendicular lean mass
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (10)

Descriptor	Name	Tree numbers
D020788	Bardet-Biedl Syndrome	C10.228.140.617.200; C11.270.684.624; C16.131.077.245.125; C16.320.184.125
D003398	Craniosynostoses	C05.116.099.370.894.232; C05.660.207.240; C05.660.906.364; C16.131.621.207.240; C16.131.621.906.364
D012734	Disorders of Sex Development	C12.050.351.875.253; C12.200.706.316; C12.800.316; C16.131.939.316; C19.391.119
D015841	Enophthalmos	C11.675.319
D016142	Holoprosencephaly	C05.660.207.410; C10.500.034.875; C16.131.077.410; C16.131.260.380; C16.131.621.207.410; C16.131.666.034.875; C16.320.180.380
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D002538	Intracranial Arteriovenous Malformations	C10.228.140.300.520; C10.500.190.500; C14.240.850.750.295; C14.240.850.875.500; C14.907.150.295; C14.907.253.560.400; C16.131.240.850.750.295; C16.131.240.850.875.500; C16.131.666.190.500
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C538435	Lubs syndrome (supp.)
C536687	Weaver syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5119 (SINGLE PROTEIN)

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

ChEMBL bioactivities

7 potent at pChembl≥5 of 13 total, top 7 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.01	Kd	9.832	nM	CHEMBL5653589
7.79	ED50	16.39	nM	CHEMBL5653589
6.04	IC50	910	nM	ZERUMBONE
5.57	IC50	2700	nM	STAUROSPORINONE
5.57	IC50	2700	nM	CHEMBL193468
5.57	IC50	2700	nM	ARCYRIAFLAVIN C
5.57	IC50	2700	nM	CHEMBL190546

PubChem BioAssay actives

6 with measured affinity, of 18 total; 6 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	2148433: Binding affinity to human GLI2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0098	uM
(2E,6E,10E)-2,6,9,9-tetramethylcycloundeca-2,6,10-trien-1-one	351771: Inhibition of Gli2-mediated transcription expressed in human PANC1 cells	ic50	0.9100	uM
6-hydroxy-3,13,23-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,22]tricosa-1,4(9),5,7,10,15,17,19,21-nonaen-12-one	351771: Inhibition of Gli2-mediated transcription expressed in human PANC1 cells	ic50	2.7000	uM
6,7-dihydroxy-3,13,23-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,22]tricosa-1,4,6,8,10,15,17,19,21-nonaene-12,14-dione	351771: Inhibition of Gli2-mediated transcription expressed in human PANC1 cells	ic50	2.7000	uM
3,13,23-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,22]tricosa-1,4,6,8,10,15,17,19,21-nonaen-12-one	351771: Inhibition of Gli2-mediated transcription expressed in human PANC1 cells	ic50	2.7000	uM
6,20-dihydroxy-3,13,23-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,22]tricosa-1,4(9),5,7,10,15,17(22),18,20-nonaene-12,14-dione	351771: Inhibition of Gli2-mediated transcription expressed in human PANC1 cells	ic50	2.7000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic Trioxide	decreases expression, decreases response to substance, increases response to substance	6
Valproic Acid	affects cotreatment, decreases expression, increases expression	5
methylmercuric chloride	increases expression, affects cotreatment	3
trichostatin A	affects cotreatment, decreases expression	3
HhAntag691	affects cotreatment, affects reaction, decreases expression, increases expression, affects response to substance (+2 more)	3
(+)-JQ1 compound	decreases response to substance, decreases reaction, increases expression, decreases expression	3
Estradiol	affects expression, affects cotreatment, increases expression	3
Tobacco Smoke Pollution	decreases expression, decreases methylation	3
Arsenic	increases expression, affects methylation, increases abundance	2
Benzo(a)pyrene	affects methylation, increases expression	2
Formaldehyde	decreases expression, affects cotreatment, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
bisphenol A	affects methylation	1
embelin	decreases expression	1
2-methyl-4-isothiazolin-3-one	decreases expression	1
2-butenal	decreases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
sodium arsenite	increases abundance, increases expression	1
benzo(e)pyrene	affects methylation, decreases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
3,4,3’,4’-tetrachlorobiphenyl	affects expression	1
aflatoxin B2	affects methylation	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
goralatide	affects cotreatment, decreases reaction, increases expression	1
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	affects cotreatment, increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	affects expression, affects methylation	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1026048	Binding	Inhibition of exogenously transfected human Gli2 delta-N-mediated transcriptional activity in mouse C3H10T1/2 cells after 24 hrs by luciferase reporter gene assay	Structure-activity relationships and cancer-cell selective toxicity of novel inhibitors of glioma-associated oncogene homologue 1 (Gli1) mediated transcription. — J Med Chem

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8GU	Abcam HCT 116 GLI2 KO	Cancer cell line	Male
CVCL_B8WB	Abcam MCF-7 GLI2 KO	Cancer cell line	Female
CVCL_B9J3	Abcam A-549 GLI2 KO	Cancer cell line	Male
CVCL_E0DS	Ubigene HeLa GLI2 KO	Cancer cell line	Female
CVCL_XV65	HEK293 eGFP-GLI2	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00722436	PHASE4	TERMINATED	Tranexamic Acid for Craniofacial Surgery
NCT02188576	PHASE4	COMPLETED	The Efficacy and Population Pharmacokinetics of Tranexamic Acid for Craniosynostosis Surgery
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT03746522	PHASE3	COMPLETED	Setmelanotide (RM-493), Melanocortin-4 Receptor (MC4R) Agonist, in Bardet-Biedl Syndrome (BBS) and Alström Syndrome (AS) Participants With Moderate to Severe Obesity
NCT04966741	PHASE3	COMPLETED	Setmelanotide in Pediatric Participants With Rare Genetic Diseases of Obesity
NCT05194124	PHASE3	COMPLETED	Phase 3 Crossover Trial of Two Formulations of Setmelanotide in Participants With Specific Gene Defects in the MC4R Pathway
NCT06760546	PHASE3	RECRUITING	A Trial of Setmelanotide in Patients With Congenital Hypothalamic Obesity (Sub-study of NCT05774756)
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02229968	PHASE2	ACTIVE_NOT_RECRUITING	Efficacy of Amicar for Children Having Craniofacial Surgery
NCT03490019	PHASE2	WITHDRAWN	Treatment of Bardet-Biedl-Syndrome With Metformin for Evaluation of a Possible Visual Improvement
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT03171818	PHASE2	UNKNOWN	Darbepoetin for Ischemic Neonatal Stroke to Augment Regeneration
NCT03718234	PHASE1	COMPLETED	Subcutaneous Hydrocortisone Children With Congenital Adrenal Hyperplasia
NCT00912119	PHASE1	COMPLETED	Amicar Pharmacokinetics of Children Having Craniofacial Surgery
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT00005016	Not specified	COMPLETED	Study of the Experiences and Needs of Parents Continuing a Pregnancy Following a Prenatal Diagnosis of Holopresencephaly
NCT00088426	Not specified	COMPLETED	Clinical and Genetic Studies on Holoprosencephaly
NCT00645645	Not specified	COMPLETED	A Study of the Genetic Analysis of Brain Disorders
NCT04691414	Not specified	COMPLETED	Retrospective Study Using Next Generation Sequencing (NGS) on Biological Samples to Improve Genetic Counseling for Patients With Previously Explored Craniofacial Midline Defects.
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT00520078	Not specified	UNKNOWN	Clinicopathological and Molecular Correlation of Acrochordon in Relation to Human Papillomavirus Infection
NCT04161274	Not specified	COMPLETED	Randomized Clinical Trial on Skin Tags Approachment.
NCT05353374	Not specified	COMPLETED	Effectiveness of Sodium Fusidate Ointment Compared to Petrolatum for Wound Healing Following Cauterization
NCT06315946	Not specified	COMPLETED	Efficacy of a Cryogenic Medical Device on Skin Tags Versus a Comparator Product.
NCT07355543	Not specified	RECRUITING	Evaluate the Effectiveness and Safety of a Cryogenic Pen to Treat Skin Tags Versus a Comparator.
NCT04931056	Not specified	COMPLETED	A Post Market Clinical Follow-up Study on Biomet Microfixation HTR PEKK (Midface), Facial & Mandibular Plates.
NCT00485186	Not specified	WITHDRAWN	Gene Polymorphisms Influencing Steroid Synthesis and Action
NCT01875640	Not specified	COMPLETED	Decision Support for Parents Receiving Information About Child’s Rare Disease
NCT02784184	Not specified	UNKNOWN	COPENHAGEN Minipuberty Study
NCT03102554	Not specified	ENROLLING_BY_INVITATION	Genetics of Differences of Sex Development and Hypospadias