GLI3
Chr 7ADGLI family zinc finger 3
Also known as: ACLS, GCPS, GLI3-190, GLI3FL, PAP-A, PAPA, PAPA1, PAPB
This gene encodes GLI3, a zinc finger transcription factor that acts as both an activator and repressor in the sonic hedgehog signaling pathway and is essential for proper limb development and digit formation. Mutations cause autosomal dominant conditions including Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, and various forms of polydactyly, all characterized by limb malformations and often craniofacial abnormalities. The gene is highly constrained against loss-of-function variants in the general population, reflecting its critical role in development.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Mild missense constraint
This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
100 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 4 | 0 | 0 | 0 | 4 |
Likely Pathogenic | 2 | 2 | 0 | 0 | 4 |
VUS | 1 | 69 | 1 | 0 | 71 |
Likely Benign | 0 | 4 | 0 | 3 | 7 |
Benign | 0 | 0 | 0 | 0 | 0 |
Conflicting | — | 3 | |||
| Total | 7 | 75 | 1 | 3 | 89 |
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.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools