GLI3

Summary

GLI3 (GLI family zinc finger 3, HGNC:4319) is a protein-coding gene on chromosome 7p14.1, encoding Transcriptional activator GLI3 (P10071). Has a dual function as a transcriptional activator and a repressor of the sonic hedgehog (Shh) pathway, and plays a role in limb development. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a protein which belongs to the C2H2-type zinc finger proteins subclass of the Gli family. They are characterized as DNA-binding transcription factors and are mediators of Sonic hedgehog (Shh) signaling. The protein encoded by this gene localizes in the cytoplasm and activates patched Drosophila homolog (PTCH) gene expression. It is also thought to play a role during embryogenesis. Mutations in this gene have been associated with several diseases, including Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, preaxial polydactyly type IV, and postaxial polydactyly types A1 and B.

Source: NCBI Gene 2737 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Greig cephalopolysyndactyly syndrome (Definitive, ClinGen) — +6 more curated relationships
• GWAS associations: 21
• Clinical variants (ClinVar): 1,531 total — 151 pathogenic, 56 likely-pathogenic
• Phenotypes (HPO): 201
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 142 downstream targets (CollecTRI)
• MANE Select transcript: NM_000168

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4319
Approved symbol	GLI3
Name	GLI family zinc finger 3
Location	7p14.1
Locus type	gene with protein product
Status	Approved
Aliases	PAP-A, PAPA, PAPA1, PAPB, ACLS, PPDIV
Ensembl gene	ENSG00000106571
Ensembl biotype	protein_coding
OMIM	165240
Entrez	2737

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 13 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000395925, ENST00000428534, ENST00000437480, ENST00000464291, ENST00000479210, ENST00000642432, ENST00000643264, ENST00000647255, ENST00000677288, ENST00000677605, ENST00000677990, ENST00000678429, ENST00000678978, ENST00000878750, ENST00000878751, ENST00000911414

RefSeq mRNA: 1 — MANE Select: NM_000168 NM_000168

CCDS: CCDS5465

Canonical transcript exons

ENST00000395925 — 15 exons

Exon	Start	End
ENSE00001523264	41960949	41966641
ENSE00001523285	42223130	42223295
ENSE00001523287	42236971	42237209
ENSE00003467890	42076752	42076857
ENSE00003495688	42045384	42045530
ENSE00003503359	41977558	41977722
ENSE00003517490	41967596	41967923
ENSE00003530488	41978599	41978748
ENSE00003537008	41972337	41972627
ENSE00003541133	42026199	42026412
ENSE00003554136	42025264	42025377
ENSE00003638309	42148226	42148468
ENSE00003650203	42048491	42048696
ENSE00003656988	42023468	42023608
ENSE00003684714	42040038	42040239

Expression profiles

Bgee: expression breadth ubiquitous, 263 present calls, max score 98.53.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.0797 / max 373.2304, expressed in 1295 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
83780	6.7259	1102
83781	4.0126	1090
83783	0.3678	134
83779	0.3329	184
204422	0.2794	84
83782	0.2326	75
83776	0.0904	40
83777	0.0380	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	98.53	gold quality
olfactory bulb	UBERON:0002264	95.31	silver quality
tendon of biceps brachii	UBERON:0008188	94.58	gold quality
tibia	UBERON:0000979	93.94	gold quality
ganglionic eminence	UBERON:0004023	93.65	gold quality
embryo	UBERON:0000922	92.42	gold quality
type B pancreatic cell	CL:0000169	91.81	gold quality
parietal pleura	UBERON:0002400	91.40	gold quality
nipple	UBERON:0002030	91.35	gold quality
diaphragm	UBERON:0001103	91.10	gold quality
triceps brachii	UBERON:0001509	90.86	silver quality
gluteal muscle	UBERON:0002000	90.40	silver quality
buccal mucosa cell	CL:0002336	89.95	gold quality
cauda epididymis	UBERON:0004360	89.45	gold quality
skin of hip	UBERON:0001554	89.38	gold quality
lateral globus pallidus	UBERON:0002476	88.76	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	88.74	gold quality
mammalian vulva	UBERON:0000997	88.55	gold quality
mammary duct	UBERON:0001765	88.46	gold quality
synovial joint	UBERON:0002217	88.42	gold quality
pleura	UBERON:0000977	88.22	gold quality
layer of synovial tissue	UBERON:0007616	87.94	gold quality
placenta	UBERON:0001987	87.88	gold quality
substantia nigra pars reticulata	UBERON:0001966	87.79	silver quality
parotid gland	UBERON:0001831	87.66	silver quality
epithelium of mammary gland	UBERON:0003244	87.43	gold quality
subthalamic nucleus	UBERON:0001906	87.34	silver quality
hair follicle	UBERON:0002073	87.04	silver quality
cardia of stomach	UBERON:0001162	86.95	gold quality
penis	UBERON:0000989	86.87	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-75140	yes	750.01
E-GEOD-93593	yes	119.11
E-GEOD-109979	yes	53.56
E-HCAD-5	yes	42.98
E-ANND-3	yes	13.38
E-MTAB-10485	no	185.91

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

142 targets.

Target	Regulation
ABCB1
ADAM2
AGRN
AKR1A1
ALYREF
AMY2A
APBB1
AR
ASH1L
ATCAY
ATM
ATP11C
AVP
BCL2	Unknown
CCND1	Unknown
CD5	Unknown
CD74
CD79A
CD82
CDK1
CDK6	Repression
CDKN1A
CDKN2C	Activation
CHD1
CHD4
CHD8
COL10A1	Activation
COMP
CP
CSE1L

JASPAR motifs

Motif	Name	Family
MA1491.1	GLI3	More than 3 adjacent zinc fingers
MA1491.2	GLI3	More than 3 adjacent zinc fingers
MA1491.3	GLI3	More than 3 adjacent zinc fingers

JASPAR matrix evidence (PMIDs): PMID:2105456

Upstream regulators (CollecTRI, top): CTNNB1, CXCL1, EN1, ETV4, GLI3, HAND2, PBX1, SOX2, SPOP

miRNA regulators (miRDB)

166 targeting GLI3, 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-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-4455	100.00	65.48	1587
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-124-3P	99.89	73.74	3043

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• This mutation, a 72-bp insertion into exon 14 of the GLI3 gene, creates a premature stop codon and predicts a truncated protein product. (PMID:12545275)
• Mutation data on GL13 are presented. (PMID:12575660)
• Mutations are described for the Pallister-Hall syndrome (syndactyly). (PMID:12575661)
• Patients with Greig cephalopolysyndactyly syndrome caused by large deletions that include GLI3 are likely to have cognitive deficits. (PMID:14608643)
• Greig cephalopolysyndactyly is an autosomal dominant condition caused by mutations of the gene GLI3, located on 7p13. (PMID:15390181)
• results demonstrate a robust correlation of genotype and phenotype for GLI3 mutations and strongly support the hypothesis that these two allelic disorders have distinct modes of pathogenesis. (PMID:15739154)
• There is direct link between phosphorylation of Gli3/Ci proteins and betaTrCP/Slimb action, thus supporting the hypothesis that the processing of Gli3/Ci is affected by the proteasome. (PMID:16371461)
• Multisite glycogen synthase kinase 3beta (GSK3beta) phosphorylation and ubiquitination by SCFbetaTrCP are required for Gli3 processing. (PMID:16705181)
• There is an association between GLI3 gene and idiopathic congenital talipes equinovarus, and exons 9,10,11,12 are not its mutation hot spots. (PMID:17029207)
• explain, at the molecular level, why Gli2 and Gli3 are differentially processed (PMID:17283082)
• A Gli3 mutant allele transgene that expresses only the full-length form can rescue the sonic hedgehog (Shh) mutant digit phenotype to a great extent. (PMID:17400206)
• Assays of deletion constructs revealed that the human-Fugu conserved sequences within the GLI3 intronic CNEs were essential but not sufficient for full-scale transcriptional activation (PMID:17426814)
• Characterization of the interactions of human ZIC3 mutants with GLI3 (PMID:17764085)
• SALL1 and GLI3 may have roles in limb malformation and are affected by nonsense-mediated decay (PMID:18000979)
• Gli3, by acting as a transcriptional repressor, restricted graded Shh/Gli ventral activity to properly pattern the spinal cord. (PMID:18057099)
• This study strongly suggests that sporadic hypothalamic hamartomas can be due to somatic mutations in the sonic hedgehog pathway. Malformations of cortical development are usually sporadic, and intrauterine insults are often regarded as the cause. (PMID:18057317)
• The development of chromosomal abnormalities within GLI3 is associated with the pathogenesis of hypothalamic hamartoma (HH) lesions in sporadic, nonsyndromic patients with HH and intractable epilepsy. (PMID:18252217)
• Tested variants are not associated with anorectal malformations and most are predicted to be benign. (PMID:18655123)
• Results suggest that the growth-promoting role of IGFBP-2 in prostate cancer is inhibited by its intracellular interaction with PAPA-1. (PMID:19095771)
• cytoplasmic Gli-3 was overexpressed in 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)
• Gli3 regulates angiogenesis and endothelial cell activity in adult mammals. (PMID:19729595)
• GLI3 point mutations lead to misregulation of its subcellular localization (PMID:19829694)
• The expression of Gli3, regulated by HOXD13, may play a role in idiopathic congenital talipes equinovarus. (PMID:19925654)
• 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)
• GLI3 is preferentially expressed by human bulge cells, compared to differentiated hair follicle keratinocytes (PMID:20050020)
• relationship between mutation points of GLI3 & Gli3 & resulting phenotypes in humans & mice described; discussed how reduced amounts of GLI3 protein or truncated mutant GLI3 protein disrupt development of limbs, head, face [review] (PMID:20201963)
• Pallister-Hall syndrome includes bifid epiglottis, hypothalamic hamartoblastoma, postaxial polydactyly, anal atresia, and occasionally laryngeal clefts. Mutations in the GLI3 gene can cause Pallister-Hall syndrome (PMID:20425471)
• These results not only demonstrate the high level of complexity in the genetic mechanisms controlling Gli3 expression, but also reveal the evolutionary significance of cis-acting regulatory networks of early developmental regulators in vertebrates. (PMID:20426846)
• study reports on the novel association of trigonocephaly and polysyndactyly in two unrelated patients due to mutations within the last third (exon 14) and first third (exon 6) of the GLI3 gene, respectively (PMID:20583172)
• The phenotype spectrum of GL13 mutations is broader than encompassed by clinical diagnostic criteria in Greig cephalopolysyndactyly and Pallister-Hall syndromes (GCPS, PHS) patients than previously recognized. (PMID:20672375)
• Pias1-dependent SUMOylation influences Gli protein activity (PMID:20711444)
• Disruption of Gli3-Zic3 interaction in the critical period for ventral body wall formation may contribute to omphalocele phenotype in Cd chick model. (PMID:21069353)
• Clinical and molecular findings of previously reported patients who had GLI3 mutations and genital abnormalities were reviewed. (PMID:21108399)
• ciliary localization of Sufu is dependent on ciliary-localized Gli proteins, and is inhibited by PKA activation (PMID:21209912)
• a novel mutation of GLI3 causing various digital abnormalities (PMID:21320477)
• association of intragenic GLI3 mutations with metopic synostosis (PMID:21326280)
• GLI3 is strongly expressed by virtually 100% of the Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma. (PMID:21531006)
• A three-part signal governs differential processing of Gli1 and Gli3 proteins by the proteasome. (PMID:21921029)
• loss of Gli3 signaling leads to disruption of the MDM2-p53 interaction and strongly potentiates p53-dependent cell growth inhibition in colon cancer cells (PMID:22227409)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gli3	ENSDARG00000052131
mus_musculus	Gli3	ENSMUSG00000021318
rattus_norvegicus	Gli3	ENSRNOG00000014395

Paralogs (14): ZIC2 (ENSG00000043355), ZXDC (ENSG00000070476), GLI2 (ENSG00000074047), 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

Transcriptional activator GLI3 — P10071 (reviewed: P10071)

Alternative names: GLI3 form of 190 kDa, GLI3 full-length protein

All UniProt accessions (8): P10071, A0A2R8Y6R3, A0A2R8Y723, A0A2R8YGX0, A0A7I2V3B8, A0A7I2V4V2, A0A7I2V4X9, F8WEV4

UniProt curated annotations — full annotation on UniProt →

Function. Has a dual function as a transcriptional activator and a repressor of the sonic hedgehog (Shh) pathway, and plays a role in limb development. The full-length GLI3 form (GLI3FL) after phosphorylation and nuclear translocation, acts as an activator (GLI3A) while GLI3R, its C-terminally truncated form, acts as a repressor. A proper balance between the GLI3 activator and the repressor GLI3R, rather than the repressor gradient itself or the activator/repressor ratio gradient, specifies limb digit number and identity. In concert with TRPS1, plays a role in regulating the size of the zone of distal chondrocytes, in restricting the zone of PTHLH expression in distal cells and in activating chondrocyte proliferation. Binds to the minimal GLI-consensus sequence 5’-GGGTGGTC-3'.

Subunit / interactions. The full-length GLI3 form (GLI3FL) interacts with SUFU and this interaction regulates the formation of either repressor or activator forms of GLI3. Its association with SUFU is regulated by Hh signaling and dissociation of the SUFU-GLI3 interaction requires the presence of the ciliary motor KIF3A. Interacts with KIF7. The activator form of GLI3 (GLI3A) but not the repressor form (GLI3R) can interact with TRPS1. The phosphorylated form interacts with BTRC. Interacts with ZIC1. Interacts with ZIC3 (via C2H2-type domains 3, 4 and 5); the interaction enhances its transcriptional activity. Interacts with WRD11; the interaction associates EMX1 with GLI3. Interacts with DZIP1; retains GLI3 within the cytoplasm. Interacts with TMEM216; this interaction reduces nuclear localization of GLI3.

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

Tissue specificity. Is expressed in a wide variety of normal adult tissues, including lung, colon, spleen, placenta, testis, and myometrium.

Post-translational modifications. Phosphorylated on multiple sites by protein kinase A (PKA) and phosphorylation by PKA primes further phosphorylation by CK1 and GSK3. Phosphorylated by DYRK2 (in vitro). Phosphorylation is essential for its proteolytic processing. Transcriptional repressor GLI3R, a C-terminally truncated form, is generated from the full-length GLI3 protein (GLI3FL/GLI3-190) through proteolytic processing. This process requires PKA-primed phosphorylation of GLI3, ubiquitination of GLI3 and the presence of BTRC. GLI3FL is complexed with SUFU in the cytoplasm and is maintained in a neutral state. Without the Hh signal, the SUFU-GLI3 complex is recruited to cilia, leading to the efficient processing of GLI3FL into GLI3R. GLI3R formation leads to its dissociation from SUFU, allowing it to translocate into the nucleus, and repress Hh target genes. When Hh signaling is initiated, SUFU dissociates from GLI3FL and this has two consequences. First, GLI3R production is halted. Second, free GLI3FL translocates to the nucleus, where it is phosphorylated, destabilized, and converted to a transcriptional activator (GLI3A). Phosphorylated in vitro by ULK3.

Disease relevance. Greig cephalo-poly-syndactyly syndrome (GCPS) [MIM:175700] Autosomal dominant disorder affecting limb and craniofacial development. It is characterized by pre- and postaxial polydactyly, syndactyly of fingers and toes, macrocephaly and hypertelorism. The disease is caused by variants affecting the gene represented in this entry. Pallister-Hall syndrome (PHS) [MIM:146510] An autosomal dominant disorder characterized by a wide range of clinical manifestations. Clinical features include hypothalamic hamartoma, pituitary dysfunction, central or postaxial polydactyly, and syndactyly. Malformations are frequent in the viscera, e.g. anal atresia, bifid uvula, congenital heart malformations, pulmonary or renal dysplasia. The disease is caused by variants affecting the gene represented in this entry. Polydactyly, postaxial A1 (PAPA1) [MIM:174200] A condition characterized by the occurrence of supernumerary digits in the upper and/or lower extremities. In postaxial polydactyly type A, the extra digit is well-formed and articulates with the fifth or a sixth metacarpal/metatarsal. The disease is caused by variants affecting the gene represented in this entry. Polydactyly, postaxial B (PAPB) [MIM:174200] A condition characterized by an extra digit in the occurrence of supernumerary digits in the upper and/or lower extremities. In postaxial polydactyly type B the extra digit is not well formed and is frequently in the form of a skin. The disease is caused by variants affecting the gene represented in this entry. Polydactyly, preaxial 4 (PPD4) [MIM:174700] A form of polydactyly, a condition defined by the occurrence of supernumerary digits in the upper and/or lower extremities. Preaxial or radial polydactyly refers to the presence of extra digits on the radial side of the hand. PPD4 is an autosomal dominant form characterized by mild duplication of the thumb, syndactyly of various degrees affects fingers 3 and 4, duplication of part or all of the first or second toes and variable toes syndactyly. Some patients have only foot involvement. The disease is caused by variants affecting the gene represented in this entry.

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

RefSeq proteins (1): NP_000159* (*=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 (69 total): mutagenesis site 16, sequence variant 14, compositionally biased region 9, modified residue 9, cross-link 7, region of interest 6, zinc finger region 5, chain 2, strand 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4BLD	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P10071-F1	42.92	0.02

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 (16): 1, 175, 664, 849, 865, 877, 907, 980, 1006, 438, 462, 773, 779, 779, 784, 800

Mutagenesis-validated functional residues (16):

Position	Phenotype
773	loss of proteolytic processing.
779	loss of proteolytic processing.
784	loss of proteolytic processing.
800	loss of proteolytic processing.
849	loss of phosphorylation and proteolytic processing.
855	loss of proteolytic processing.
856	loss of proteolytic processing.
861	loss of proteolytic processing.
864	loss of proteolytic processing.
865	loss of phosphorylation and proteolytic processing.
873	loss of proteolytic processing.
877	loss of phosphorylation and proteolytic processing.
903	loss of proteolytic processing.
907	loss of phosphorylation and proteolytic processing.
980	loss of phosphorylation and proteolytic processing.
1006	loss of phosphorylation and proteolytic processing.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-5610785	GLI3 is processed to GLI3R 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-8940973	RUNX2 regulates osteoblast differentiation

MSigDB gene sets: 894 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GOBP_SPINAL_CORD_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_MAMMARY_GLAND_MORPHOGENESIS, GOBP_NEGATIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_GLAND_MORPHOGENESIS, GOBP_BEHAVIOR, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_METANEPHROS_DEVELOPMENT

GO Biological Process (109): negative regulation of transcription by RNA polymerase II (GO:0000122), osteoblast differentiation (GO:0001649), metanephros development (GO:0001656), branching involved in ureteric bud morphogenesis (GO:0001658), in utero embryonic development (GO:0001701), positive regulation of neuroblast proliferation (GO:0002052), chondrocyte differentiation (GO:0002062), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), protein import into nucleus (GO:0006606), smoothened signaling pathway (GO:0007224), neuroblast proliferation (GO:0007405), axon guidance (GO:0007411), hindgut morphogenesis (GO:0007442), heart development (GO:0007507), anterior/posterior pattern specification (GO:0009952), proximal/distal pattern formation (GO:0009954), protein processing (GO:0016485), optic nerve morphogenesis (GO:0021631), hippocampus development (GO:0021766), smoothened signaling pathway involved in ventral spinal cord interneuron specification (GO:0021775), smoothened signaling pathway involved in spinal cord motor neuron cell fate specification (GO:0021776), forebrain dorsal/ventral pattern formation (GO:0021798), layer formation in cerebral cortex (GO:0021819), forebrain radial glial cell differentiation (GO:0021861), lateral ganglionic eminence cell proliferation (GO:0022018), melanocyte differentiation (GO:0030318), lung development (GO:0030324), negative regulation of chondrocyte differentiation (GO:0032331), positive regulation of chondrocyte differentiation (GO:0032332), T cell differentiation in thymus (GO:0033077), limb morphogenesis (GO:0035108), positive regulation of protein import into nucleus (GO:0042307), odontogenesis of dentin-containing tooth (GO:0042475), embryonic digit morphogenesis (GO:0042733), negative regulation of apoptotic process (GO:0043066), nose morphogenesis (GO:0043585), tongue development (GO:0043586), negative thymic T cell selection (GO:0045060), negative regulation of neuron differentiation (GO:0045665)

GO Molecular Function (16): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), chromatin binding (GO:0003682), DNA-binding transcription factor activity (GO:0003700), beta-catenin binding (GO:0008013), zinc ion binding (GO:0008270), histone acetyltransferase binding (GO:0035035), mediator complex binding (GO:0036033), histone deacetylase binding (GO:0042826), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), double-stranded DNA binding (GO:0003690), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565), metal ion binding (GO:0046872)

GO Cellular Component (13): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), cilium (GO:0005929), axoneme (GO:0005930), nuclear speck (GO:0016607), transcription repressor complex (GO:0017053), ciliary tip (GO:0097542), ciliary base (GO:0097546), GLI-SUFU complex (GO:1990788), 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	7
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
cell differentiation	2
regulation of DNA-templated transcription	2
regionalization	2
transcription cis-regulatory region binding	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
binding	2
enzyme binding	2
DNA binding	2
nuclear lumen	2
cilium	2
negative regulation of DNA-templated transcription	1
ossification	1
kidney development	1
branching morphogenesis of an epithelial tube	1
ureteric bud morphogenesis	1
chordate embryonic development	1
neuroblast proliferation	1
positive regulation of neurogenesis	1
regulation of neuroblast proliferation	1
positive regulation of neural precursor cell proliferation	1
cartilage development	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
cell surface receptor signaling pathway	1
generation of neurons	1
neural precursor cell proliferation	1
axonogenesis	1
neuron projection guidance	1
anatomical structure morphogenesis	1
digestive tract morphogenesis	1
hindgut development	1
animal organ development	1

Protein interactions and networks

STRING

2678 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GLI3	SUFU	Q9UMX1	997
GLI3	SHH	Q15465	963
GLI3	PTCH1	Q13635	955
GLI3	SMO	Q99835	945
GLI3	KIF7	Q2M1P5	919
GLI3	RAB23	Q9ULC3	881
GLI3	FOXF1	Q12946	822
GLI3	IHH	Q14623	818
GLI3	GSK3B	P49841	813
GLI3	DHH	O43323	799
GLI3	HHIP	Q96QV1	790
GLI3	KIF27	Q86VH2	787
GLI3	STK36	Q9NRP7	758
GLI3	PTCH2	Q9Y6C5	752
GLI3	AKT1	P31749	746

IntAct

34 interactions, top by confidence:

A	B	Type	Score
GLI3	SUFU	psi-mi:“MI:0407”(direct interaction)	0.770
SUFU	GLI3	psi-mi:“MI:0407”(direct interaction)	0.770
GLI3	STK36	psi-mi:“MI:2364”(proximity)	0.540
GLI3	STK36	psi-mi:“MI:0915”(physical association)	0.540
GLI3	Zic1	psi-mi:“MI:0915”(physical association)	0.520
Zic2	GLI3	psi-mi:“MI:0915”(physical association)	0.520
GLI3	Zic2	psi-mi:“MI:0915”(physical association)	0.520
GLI3	Spop	psi-mi:“MI:0915”(physical association)	0.400
GLI3	SKIL	psi-mi:“MI:0915”(physical association)	0.400
GLI3	Zic3	psi-mi:“MI:0915”(physical association)	0.400
Sufu	GLI3	psi-mi:“MI:0915”(physical association)	0.370
Pias1	GLI3	psi-mi:“MI:0915”(physical association)	0.370
EGLN3	FAM168B	psi-mi:“MI:0914”(association)	0.350
THSD4	KRBA1	psi-mi:“MI:0914”(association)	0.350
CELA1	KRBA1	psi-mi:“MI:0914”(association)	0.350
RCCD1	ZNF609	psi-mi:“MI:0914”(association)	0.350
WDR11	GLI3	psi-mi:“MI:0914”(association)	0.350
SOX2	CBX4	psi-mi:“MI:0914”(association)	0.350
GLI2	SPOP	psi-mi:“MI:0914”(association)	0.350
GLI3	SPOP	psi-mi:“MI:0914”(association)	0.350
CSNK2A2	VWA8	psi-mi:“MI:0914”(association)	0.350
GLI3	YWHAE	psi-mi:“MI:0914”(association)	0.350
TOMM20	NUDT19	psi-mi:“MI:2364”(proximity)	0.270
GLI3	CNOT1	psi-mi:“MI:2364”(proximity)	0.270
GLI3	SMAD1	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (113): GLI3 (Reconstituted Complex), GLI3 (Affinity Capture-MS), GLI3 (Synthetic Lethality), GLI3 (Co-localization), GLI3 (Co-localization), GLI3 (Affinity Capture-Western), USP7 (Affinity Capture-Western), GLI3 (Co-crystal Structure), GLI3 (Protein-peptide), GLI3 (Reconstituted Complex), GLI3 (Biochemical Activity), GLI3 (Affinity Capture-MS), GLI3 (Affinity Capture-MS), GLI3 (Affinity Capture-MS), GLI3 (Affinity Capture-MS)

ESM2 similar proteins: A0A096MJY4, A0A486WWJ9, A2ICN5, A2VDZ3, A4UTP7, A8WL06, B7ZR65, H2LBU8, O89038, P10071, P40791, P55197, P55879, Q02078, Q03413, Q03414, Q06413, Q0VGT2, Q14814, Q2KIA0, Q2MJT0, Q32NP8, Q4VYR7, Q5IS56, Q5R444, Q5REW7, Q5U4X3, Q60929, Q61602, Q63943, Q6DFF5, Q6DIF3, Q6F2E7, Q7ZY13, Q8BUR3, Q8CFN5, Q91660, Q91661, Q9DE25, Q9EPK5

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

38 interactions.

A	Effect	B	Mechanism
ZIC1	up-regulates	GLI3	relocalization
ZIC1	up-regulates	GLI3
CSNK1A1	down-regulates	GLI3	phosphorylation
RAB23	down-regulates	GLI3
BTRC	“down-regulates quantity by destabilization”	GLI3	ubiquitination
CSNK1A1L	up-regulates	GLI3	phosphorylation
CXCL1	“up-regulates quantity by expression”	GLI3	“transcriptional regulation”
GLI3	down-regulates	MED12	binding
GLI3	“up-regulates quantity by expression”	CCND1	“transcriptional regulation”
GLI3	“down-regulates quantity by repression”	MYCN	“transcriptional regulation”
GLI3	“up-regulates quantity by expression”	PTCH1	“transcriptional regulation”
PRKACA	down-regulates	GLI3	phosphorylation
ZIC3	up-regulates	GLI3	binding
ULK3	“up-regulates activity”	GLI3	phosphorylation
SPOP	“down-regulates quantity”	GLI3	ubiquitination
SUFU	“up-regulates quantity by stabilization”	GLI3	binding
SUFU	down-regulates	GLI3	relocalization
PRKACA	“down-regulates quantity”	GLI3	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

1531 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	151
Likely pathogenic	56
Uncertain significance	617
Likely benign	335
Benign	149

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070264	NC_000007.13:g.(?42187805)(42262872_?)del	Pathogenic
1072387	NC_000007.13:g.(?42116331)(42188087_?)del	Pathogenic
1072899	NM_000168.6(GLI3):c.2090del (p.Ala697fs)	Pathogenic
1075151	NM_000168.6(GLI3):c.3365_3366del (p.Val1122fs)	Pathogenic
1120232	NM_000168.6(GLI3):c.4172del (p.Gly1391fs)	Pathogenic
1120233	NM_000168.6(GLI3):c.1999C>T (p.Arg667Ter)	Pathogenic
1120234	NM_000168.6(GLI3):c.1880_1881del (p.His627fs)	Pathogenic
1120235	NM_000168.6(GLI3):c.1793dup (p.Asn598fs)	Pathogenic
1120236	NM_000168.6(GLI3):c.366C>A (p.Tyr122Ter)	Pathogenic
1120237	NM_000168.6(GLI3):c.650C>G (p.Ser217Ter)	Pathogenic
1120238	NM_000168.6(GLI3):c.1033_1048del (p.Ala345fs)	Pathogenic
1120239	NM_000168.6(GLI3):c.2103+2T>A	Pathogenic
1120241	NM_000168.6(GLI3):c.1133dup (p.Pro379fs)	Pathogenic
1120243	NM_000168.6(GLI3):c.3667_3670delinsATCAA (p.Tyr1223fs)	Pathogenic
1120244	NM_000168.6(GLI3):c.2059del (p.Glu687fs)	Pathogenic
1177290	NM_000168.6(GLI3):c.368-459_473+494del	Pathogenic
1320114	NM_000168.6(GLI3):c.3325G>T (p.Glu1109Ter)	Pathogenic
1320134	NM_000168.6(GLI3):c.2598del (p.Ile867fs)	Pathogenic
1323018	NM_000168.6(GLI3):c.3437_3453del (p.Leu1146fs)	Pathogenic
1350813	NM_000168.6(GLI3):c.4413del (p.Thr1472fs)	Pathogenic
1358687	NM_000168.6(GLI3):c.602_675del (p.Met201fs)	Pathogenic
13813	NC_000007.14:g.(?41960949)(42264268_?)del	Pathogenic
13814	NM_000168.6(GLI3):c.2023del (p.Glu675fs)	Pathogenic
13815	NM_000168.6(GLI3):c.2012del (p.Gly671fs)	Pathogenic
1381542	NM_000168.6(GLI3):c.4507C>T (p.Gln1503Ter)	Pathogenic
13816	GLI3, CODON 764, FS	Pathogenic
13817	NM_000168.6(GLI3):c.3646dup (p.Leu1216fs)	Pathogenic
13818	NM_000168.6(GLI3):c.3439G>T (p.Glu1147Ter)	Pathogenic
13819	NM_000168.6(GLI3):c.3707del (p.Gly1236fs)	Pathogenic
13820	NM_000168.6(GLI3):c.1927C>T (p.Arg643Ter)	Pathogenic

SpliceAI

4063 predictions. Top by Δscore:

Variant	Effect	Δscore
7:41978597:A:AC	donor_gain	1.0000
7:41978598:C:CC	donor_gain	1.0000
7:41978598:CAGTG:C	donor_gain	1.0000
7:41978744:ATATG:A	acceptor_gain	1.0000
7:41978745:TATG:T	acceptor_gain	1.0000
7:41978747:TG:T	acceptor_gain	1.0000
7:41978749:C:CC	acceptor_gain	1.0000
7:41978754:G:GC	acceptor_gain	1.0000
7:41978756:T:C	acceptor_gain	1.0000
7:41978756:T:TC	acceptor_gain	1.0000
7:42023462:ACTTA:A	donor_loss	1.0000
7:42023463:CTTA:C	donor_loss	1.0000
7:42023466:A:AC	donor_gain	1.0000
7:42023467:C:CC	donor_gain	1.0000
7:42023467:C:CG	donor_loss	1.0000
7:42023467:CGTG:C	donor_gain	1.0000
7:42023604:TGTTC:T	acceptor_gain	1.0000
7:42023605:GTTC:G	acceptor_gain	1.0000
7:42023606:TTC:T	acceptor_gain	1.0000
7:42023607:TC:T	acceptor_gain	1.0000
7:42023608:CC:C	acceptor_gain	1.0000
7:42023609:C:CC	acceptor_gain	1.0000
7:42025388:CATT:C	acceptor_gain	1.0000
7:42025391:T:C	acceptor_gain	1.0000
7:42025391:T:TC	acceptor_gain	1.0000
7:42025394:C:CT	acceptor_gain	1.0000
7:42025400:C:CT	acceptor_gain	1.0000
7:42025400:C:T	acceptor_gain	1.0000
7:42025401:A:T	acceptor_gain	1.0000
7:42040033:CATA:C	donor_loss	1.0000

AlphaMissense

10454 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:41972546:G:C	H632D	1.000
7:41972553:C:A	K629N	1.000
7:41972553:C:G	K629N	1.000
7:41972555:T:C	K629E	1.000
7:41972559:A:C	H627Q	1.000
7:41972559:A:T	H627Q	1.000
7:41972560:T:A	H627L	1.000
7:41972560:T:C	H627R	1.000
7:41972560:T:G	H627P	1.000
7:41972561:G:A	H627Y	1.000
7:41972561:G:C	H627D	1.000
7:41972561:G:T	H627N	1.000
7:41972562:T:A	K626N	1.000
7:41972562:T:G	K626N	1.000
7:41972563:T:A	K626I	1.000
7:41972564:T:C	K626E	1.000
7:41972564:T:G	K626Q	1.000
7:41972566:C:G	R625P	1.000
7:41972569:A:G	L624P	1.000
7:41972569:A:T	L624H	1.000
7:41972573:A:G	S623P	1.000
7:41972574:G:C	S622R	1.000
7:41972574:G:T	S622R	1.000
7:41972576:T:G	S622R	1.000
7:41972578:G:T	P621Q	1.000
7:41972581:T:A	D620V	1.000
7:41972581:T:C	D620G	1.000
7:41972581:T:G	D620A	1.000
7:41972582:C:A	D620Y	1.000
7:41972582:C:G	D620H	1.000

dbSNP variants (sampled 300 via entrez): RS1000003451 (7:42049111 GAAAGA>G,GAAAGAAAAGA), RS1000007443 (7:42088595 A>G), RS1000015752 (7:42001467 C>G), RS1000039799 (7:41966635 T>C,G), RS1000047455 (7:42019571 C>T), RS1000056076 (7:42214177 C>A,T), RS1000059314 (7:42058309 G>A), RS1000071882 (7:42207070 G>A,T), RS1000073401 (7:42148139 A>ACG), RS1000076327 (7:42133506 C>T), RS1000082738 (7:42228413 T>A), RS1000096438 (7:42127951 G>A), RS1000099291 (7:42253218 G>A), RS1000113432 (7:42187803 G>C), RS1000113957 (7:42094751 TA>T,TAA)

Disease associations

OMIM: gene MIM:165240 | disease phenotypes: MIM:146510, MIM:175700, MIM:174200, MIM:174700, MIM:123100, MIM:603596, MIM:142623, MIM:241800, MIM:142340, MIM:175500, MIM:145290, MIM:616364, MIM:619681

GenCC curated gene-disease

Disease	Classification	Inheritance
Pallister-Hall syndrome	Definitive	Autosomal dominant
Greig cephalopolysyndactyly syndrome	Definitive	Autosomal dominant
polysyndactyly 4	Strong	Autosomal dominant
polydactyly, postaxial, type A1	Strong	Autosomal dominant
acrocallosal syndrome	Supportive	Autosomal recessive
tibial hemimelia	Supportive	Autosomal dominant
postaxial polydactyly type A	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Greig cephalopolysyndactyly syndrome	Definitive	AD

Mondo (24): Pallister-Hall syndrome (MONDO:0007804), Greig cephalopolysyndactyly syndrome (MONDO:0008287), polydactyly, postaxial, type A1 (MONDO:0008266), polysyndactyly 4 (MONDO:0008272), craniosynostosis (MONDO:0015469), hepatoblastoma (MONDO:0018666), polydactyly (MONDO:0021003), postaxial polydactyly (MONDO:0020927), postaxial polydactyly type B (MONDO:0019674), Hirschsprung disease, susceptibility to, 1 (MONDO:0007723), intellectual disability (MONDO:0001071), postaxial polydactyly type A (MONDO:0019673), congenital hypothalamic hamartoma syndrome (MONDO:0009436), congenital diaphragmatic hernia (MONDO:0005711), generalized dystonia (MONDO:0000476)

Orphanet (16): Greig cephalopolysyndactyly syndrome (Orphanet:380), Pallister-Hall syndrome (Orphanet:672), Polysyndactyly (Orphanet:93338), Craniosynostosis (Orphanet:1531), Hepatoblastoma (Orphanet:449), Postaxial polydactyly type B (Orphanet:93335), Hirschsprung disease (Orphanet:388), Postaxial polydactyly type A (Orphanet:93334), Congenital diaphragmatic hernia (Orphanet:2140), Generalized isolated dystonia (Orphanet:376724), Cronkhite-Canada syndrome (Orphanet:2930), Difference of sex development (Orphanet:90771), White-Sutton syndrome (Orphanet:468678), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), Congenital hypothalamic hamartoma syndrome (Orphanet:2113)

HPO phenotypes

201 total (30 of 201 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000046	Small scrotum
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000062	Ambiguous genitalia
HP:0000072	Hydroureter
HP:0000086	Ectopic kidney
HP:0000089	Renal hypoplasia
HP:0000098	Tall stature
HP:0000107	Renal cyst
HP:0000110	Renal dysplasia
HP:0000122	Unilateral renal agenesis
HP:0000126	Hydronephrosis
HP:0000171	Microglossia
HP:0000175	Cleft palate
HP:0000191	Accessory oral frenulum
HP:0000193	Bifid uvula
HP:0000204	Cleft upper lip
HP:0000238	Hydrocephalus
HP:0000243	Trigonocephaly
HP:0000256	Macrocephaly
HP:0000260	Wide anterior fontanel
HP:0000268	Dolichocephaly
HP:0000269	Prominent occiput
HP:0000270	Delayed cranial suture closure
HP:0000273	Facial grimacing
HP:0000308	Microretrognathia
HP:0000316	Hypertelorism

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST001310_9	Allergic rhinitis	2.000000e-06
GCST001814_15	Age-related macular degeneration	9.000000e-06
GCST002308_6	Mean arterial pressure (alcohol consumption interaction)	7.000000e-07
GCST003635_6	middle facial morphology traits (quantitative measurement)	5.000000e-10
GCST003637_3	facial morphology traits (multivariate analysis)	3.000000e-07
GCST004372_1	Language performance in older adults (adjusted for episodic memory)	3.000000e-09
GCST005212_23	Asthma	4.000000e-06
GCST005748_5	Digit length ratio (right hand)	9.000000e-06
GCST005749_2	Digit length ratio (left hand)	2.000000e-06
GCST005749_8	Digit length ratio (left hand)	2.000000e-06
GCST005750_6	Digit length ratio	4.000000e-08
GCST008513_10	Health literacy	8.000000e-07
GCST008513_11	Health literacy	4.000000e-06
GCST009308_5	Emotional recognition	6.000000e-06
GCST009391_672	Metabolite levels	5.000000e-06
GCST010002_249	Refractive error	1.000000e-10
GCST010600_2	Dietary fat liking	8.000000e-06
GCST012493_2	Response to resistance training (vastus lateralis fiber area change)	2.000000e-06
GCST90000025_341	Appendicular lean mass	6.000000e-11
GCST90013406_281	Liver enzyme levels (alkaline phosphatase)	1.000000e-11
GCST90020026_562	Hip index	1.000000e-11

EFO canonical traits (14, from GWAS)

EFO ID	Trait name
EFO:0004329	alcohol drinking
EFO:0006340	mean arterial pressure
EFO:0004874	memory performance
EFO:0007710	cognitive decline measurement
EFO:0007797	language measurement
EFO:0004841	digit length ratio
EFO:0010104	health literacy measurement
EFO:0008354	cognitive function measurement
EFO:0009770	leucine measurement
EFO:0010816	dietary fat liking measurement
EFO:0600037	resistance training
EFO:0004980	appendicular lean mass
EFO:0004533	alkaline phosphatase measurement
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (15)

Descriptor	Name	Tree numbers
D055673	Acrocallosal Syndrome	C10.500.034.500; C16.131.666.034.500
D001763	Blepharoptosis	C11.338.204
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
D004422	Dystonia Musculorum Deformans	C10.228.140.079.357; C10.228.662.300.200; C10.574.500.393; C16.320.400.330
D018197	Hepatoblastoma	C04.557.435.380
D065630	Hernias, Diaphragmatic, Congenital	C16.131.433; C23.300.707.960.500.116
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D044483	Intestinal Polyposis	C06.405.469.578
D054975	Pallister-Hall Syndrome	C04.445.622; C04.588.614.250.195.885.500.299; C05.660.585.600.374; C10.228.140.211.885.500.299; C10.228.140.617.477.299; C10.551.240.250.700.500.249; C16.131.077.690; C16.131.621.585.600.374
D017689	Polydactyly	C05.660.585.600; C16.131.621.585.600
D012021	Reflex, Abnormal	C10.597.704; C23.888.592.717; E01.370.376.550.650.655; E01.370.600.550.650.655; G11.561.731.587
C535563	Absence of Tibia (supp.)
C537300	Greig cephalopolysyndactyly syndrome (supp.)
C537158	Hypothalamic hamartomas (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic	increases abundance, affects expression, affects methylation, affects cotreatment, decreases expression	4
Valproic Acid	affects expression, decreases methylation, increases expression	4
Benzo(a)pyrene	affects expression, affects methylation, decreases methylation, increases expression	3
Tobacco Smoke Pollution	decreases expression	3
bisphenol A	decreases expression, decreases methylation, increases reaction	2
trichostatin A	decreases expression, increases expression	2
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
potassium chromate(VI)	affects cotreatment, decreases expression	2
Cisplatin	decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
mono-(2-ethylhexyl)phthalate	affects expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
epigallocatechin gallate	affects cotreatment, decreases expression, increases expression	1
goralatide	affects cotreatment, decreases expression, decreases reaction	1
chromium hexavalent ion	decreases expression	1
azoxystrobin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
deguelin	decreases expression	1
fenpyroximate	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
pyrimidifen	decreases expression	1
abrine	increases expression	1
pyrachlostrobin	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
HhAntag691	decreases expression, decreases reaction	1
picoxystrobin	decreases expression	1

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B8GV	Abcam HCT 116 GLI3 KO	Cancer cell line	Male
CVCL_B9J4	Abcam A-549 GLI3 KO	Cancer cell line	Male
CVCL_E0DT	Ubigene HeLa GLI3 KO	Cancer cell line	Female
CVCL_UD91	WAe001-A-20	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06759272	PHASE4	NOT_YET_RECRUITING	Impact of CYP2C19 Genotype-guided Approach in Antiplatelet Therapy on Platelet Reactivity Index Among Coronary Artery Disease (CAD) Patients
NCT07351643	PHASE4	NOT_YET_RECRUITING	CCTA Evaluation of SGLT2i-related Pericoronary Fat Changes in Non-diabetic ACS Patients Without HF
NCT00722436	PHASE4	TERMINATED	Tranexamic Acid for Craniofacial Surgery
NCT02188576	PHASE4	COMPLETED	The Efficacy and Population Pharmacokinetics of Tranexamic Acid for Craniosynostosis Surgery
NCT02933333	PHASE4	UNKNOWN	G-CSF Alone or Combination With GM-CSF on Prevention and Treatment of Infection in Children With Malignant Tumor
NCT02343562	PHASE4	UNKNOWN	Probiotics for Prophylaxis of Postoperative Hirschsprungs Associated Enterocolitis
NCT07186647	PHASE4	COMPLETED	Laparoscopic-Assisted Transanal Pull-Through for Hirschsprung Disease in Pediatric:Short and Intermediate Outcomes of Two Different Techniques
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
NCT03017326	PHASE3	ACTIVE_NOT_RECRUITING	Paediatric Hepatic International Tumour Trial
NCT03533582	PHASE3	ACTIVE_NOT_RECRUITING	Cisplatin and Combination Chemotherapy in Treating Children and Young Adults With Hepatoblastoma or Liver Cancer After Surgery
NCT04478292	PHASE3	RECRUITING	A Multi-institutional Study for Treatment of Children With Newly Diagnosed Hepatoblastoma Using a Modified PHITT Strategy
NCT04904081	PHASE3	UNKNOWN	Feasibility of Use of Indocyanine Green in Pediatric Colorectal Surgery
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
NCT01154816	PHASE2	COMPLETED	Alisertib in Treating Young Patients With Recurrent or Refractory Solid Tumors or Leukemia
NCT02011126	PHASE2	WITHDRAWN	Imetelstat Sodium in Treating Younger Patients With Relapsed or Refractory Solid Tumors
NCT02867592	PHASE2	ACTIVE_NOT_RECRUITING	Cabozantinib-S-Malate in Treating Younger Patients With Recurrent, Refractory, or Newly Diagnosed Sarcomas, Wilms Tumor, or Other Rare Tumors
NCT03155620	PHASE2	ACTIVE_NOT_RECRUITING	Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
NCT03210714	PHASE2	ACTIVE_NOT_RECRUITING	Erdafitinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With FGFR Mutations (A Pediatric MATCH Treatment Trial)
NCT03213652	PHASE2	ACTIVE_NOT_RECRUITING	Ensartinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With ALK or ROS1 Genomic Alterations (A Pediatric MATCH Treatment Trial)
NCT03213665	PHASE2	COMPLETED	Tazemetostat in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With EZH2, SMARCB1, or SMARCA4 Gene Mutations (A Pediatric MATCH Treatment Trial)
NCT03213678	PHASE2	COMPLETED	Samotolisib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With TSC or PI3K/MTOR Mutations (A Pediatric MATCH Treatment Trial)
NCT03213704	PHASE2	ACTIVE_NOT_RECRUITING	Larotrectinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With NTRK Fusions (A Pediatric MATCH Treatment Trial)
NCT03220035	PHASE2	COMPLETED	Vemurafenib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With BRAF V600 Mutations (A Pediatric MATCH Treatment Trial)
NCT03233204	PHASE2	COMPLETED	Olaparib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Defects in DNA Damage Repair Genes (A Pediatric MATCH Treatment Trial)
NCT03526250	PHASE2	COMPLETED	Palbociclib in Treating Patients With Relapsed or Refractory Rb Positive Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Activating Alterations in Cell Cycle Genes (A Pediatric MATCH Treatment Trial)
NCT03698994	PHASE2	ACTIVE_NOT_RECRUITING	Ulixertinib in Treating Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With MAPK Pathway Mutations (A Pediatric MATCH Treatment Trial)
NCT04195555	PHASE2	ACTIVE_NOT_RECRUITING	Ivosidenib in Treating Patients With Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With IDH1 Mutations (A Pediatric MATCH Treatment Trial)
NCT04284774	PHASE2	ACTIVE_NOT_RECRUITING	Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Treatment Trial
NCT04320888	PHASE2	ACTIVE_NOT_RECRUITING	Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediatric MATCH Treatment Trial
NCT05302921	PHASE2	COMPLETED	Neoadjuvant Dual Checkpoint Inhibition and Cryoablation in Relapsed/Refractory Pediatric Solid Tumors
NCT06638931	PHASE2	RECRUITING	Agnostic Therapy in Rare Solid Tumors
NCT07300449	PHASE2	RECRUITING	A Prospective Multicenter Clinical Study of SCCG Protocol and ctDNA 5hmc in Predicting the Chemotherapy Sensitivity and Monitoring the Recurrence and Metastasis of Hepatoblastoma in Children and Adolescents
NCT00630838	PHASE2	COMPLETED	Probiotic Prophylaxis of Hirschprung’s Disease Associated Enterocolitis (HAEC)
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