GLI3

Chr 7AD

GLI family zinc finger 3

Also known as: ACLS, GCPS, GLI3-190, GLI3FL, PAP-A, PAPA, PAPA1, PAPB

NCBI Gene: 2737ENSG00000106571UniProt: P10071

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. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Greig cephalopolysyndactyly syndromeMIM #175700
AD
Pallister-Hall syndromeMIM #146510
AD
Polydactyly, postaxial, types A1 and BMIM #174200
AD
Polydactyly, preaxial, type IVMIM #174700
AD
UniProtGreig cephalo-poly-syndactyly syndrome
589
ClinVar variants
64
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— GLI3
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
64 Pathogenic / Likely Pathogenic· 327 VUS of 589 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.
0.20LOEUF
pLI 1.000
Z-score 6.17
OE 0.09 (0.05–0.20)
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.
0.52Z-score
OE missense 0.95 (0.90–1.01)
932 obs / 978.0 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.0.09 (0.05–0.20)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.95 (0.90–1.01)
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.1.12
0≤1.21.6
LoF obs/exp: 5 / 53.8Missense obs/exp: 932 / 978.0Syn Z: -2.02

ClinVar Variant Classifications

589 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic41
Likely Pathogenic23
VUS327
Likely Benign128
Benign30
Conflicting40
41
Pathogenic
23
Likely Pathogenic
327
VUS
128
Likely Benign
30
Benign
40
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
23
0
18
0
41
Likely Pathogenic
13
3
7
0
23
VUS
1
306
13
7
327
Likely Benign
0
47
21
60
128
Benign
0
12
3
15
30
Conflicting
—40
Total373686282589

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

View in ClinVar →

Protein Context — Lollipop Plot

GLI3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

GLI3-related Pallister-Hall syndrome

definitive
ADDominant NegativeAltered Gene Product Structure
Dev. DisordersSkeletal
G2P ↗

GLI3-related Greig cephalopolysyndactyly syndrome

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. DisordersSkeletal
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Greig cephalopolysyndactyly syndrome

MIM #175700

Molecular basis of disorder known

Autosomal dominant

Pallister-Hall syndrome

MIM #146510

Molecular basis of disorder known

Autosomal dominant

Polydactyly, postaxial, types A1 and B

MIM #174200

Molecular basis of disorder known

Autosomal dominant

Polydactyly, preaxial, type IV

MIM #174700

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — GLI3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
MED12 related disorders.
Graham JM Jr et al.·Am J Med Genet A
2013Review
GLI3-related polydactyly: a review.
Al-Qattan MM et al.·Clin Genet
2017Review
Polydactyly: phenotypes, genetics and classification.
Malik S·Clin Genet
2014Review
Variant characterisation and clinical profile in a large cohort of patients with Ellis-van Creveld syndrome and a family with Weyers acrofacial dysostosis.
Altunoglu U et al.·J Med Genet
2024Cohort
Preaxial polydactyly of the foot.
Burger EB et al.·Acta Orthop
2018Review
Pallister-Hall syndrome, GLI3, and kidney malformation.
McClelland K et al.·Am J Med Genet C Semin Med Genet
2022
The Greig cephalopolysyndactyly syndrome.
Biesecker LG·Orphanet J Rare Dis
2008Review
Sequential prenatal diagnosis of fetal skeletal dysplasia: A cohort study.
Jiang M et al.·Acta Obstet Gynecol Scand
2025Cohort
Germline-Somatic Liaison Dictates Cancer Subtypes via de novo Steroid Biosynthesis.
Gasperini P et al.·Cancer Discov
2025
What you can learn from one gene: GLI3.
Biesecker LG·J Med Genet
2006Review
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