GLI2

Chr 2AD

GLI family zinc finger 2

Also known as: CJS, HPE9, PHS2, THP1, THP2

NCBI Gene: 2736ENSG00000074047UniProt: P10070

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. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Culler-Jones syndromeMIM #615849
AD
Holoprosencephaly 9MIM #610829
AD
625
ClinVar variants
61
Pathogenic / LP
0.97
pLI score· haploinsufficient
0
Active trials
Clinical Summary— GLI2
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
61 Pathogenic / Likely Pathogenic· 319 VUS of 625 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.31LOEUF
pLI 0.973
Z-score 5.44
OE 0.18 (0.11–0.31)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.82Z-score
OE missense 0.93 (0.88–0.98)
896 obs / 967.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.18 (0.11–0.31)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.93 (0.88–0.98)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.96
0≤1.21.6
LoF obs/exp: 9 / 50.8Missense obs/exp: 896 / 967.5Syn Z: 0.74

ClinVar Variant Classifications

625 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic37
Likely Pathogenic24
VUS319
Likely Benign179
Benign32
Conflicting34
37
Pathogenic
24
Likely Pathogenic
319
VUS
179
Likely Benign
32
Benign
34
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
16
1
20
0
37
Likely Pathogenic
16
1
7
0
24
VUS
3
278
29
9
319
Likely Benign
0
50
29
100
179
Benign
0
4
14
14
32
Conflicting
—34
Total3533499123625

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

GLI2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

GLI2-related holoprosencephaly

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Culler-Jones syndrome

MIM #615849

Molecular basis of disorder known

Autosomal dominant

Holoprosencephaly 9

MIM #610829

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — GLI2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Holoprosencephaly.
Dubourg C et al.·Orphanet J Rare Dis
2007Review
Cohesin complex-associated holoprosencephaly.
Kruszka P et al.·Brain
2019
Phenotype and genotype of 23 patients with hypopituitarism and pathogenic GLI2 variants.
Aouchiche K et al.·Eur J Endocrinol
2025Cohort
Congenital Hypopituitarism: Various Genes, Various Phenotypes.
Xatzipsalti M et al.·Horm Metab Res
2019Review
Role of GLI2 in hypopituitarism phenotype.
Arnhold IJ et al.·J Mol Endocrinol
2015Review
GLI2 mutations as a cause of hypopituitarism.
Cohen LE·Pediatr Endocrinol Rev
2012Review
Fibroblast-derived CXCL14 aggravates crystalline silica-induced pulmonary fibrosis by mediating polarization and recruitment of interstitial macrophages.
You Y et al.·J Hazard Mater
2023
Non-canonical Hedgehog signaling mediates profibrotic hematopoiesis-stroma crosstalk in myeloproliferative neoplasms.
Pritchard JE et al.·Cell Rep
2024
GLI2-Mediated Inflammation in the Tumor Microenvironment.
Han W et al.·Adv Exp Med Biol
2020Review
Genetic disorders of the pituitary.
Cohen LE·Curr Opin Endocrinol Diabetes Obes
2012Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools