GLI3

Chr 7AD

GLI family zinc finger 3

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

NCBI Gene: 2737 ENSG00000106571 UniProt: P10071 OMIM: 165240

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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.204 OMIM phenotypes

Clinical Summary— GLI3

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Gene-Disease Validity (ClinGen)

Greig cephalopolysyndactyly syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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ClinVar Variants

212 unique Pathogenic / Likely Pathogenic· 615 VUS of 1524 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GLI3

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

0.52Z-score

OE missense 0.95 (0.90–1.01)

932 obs / 978.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.09 (0.05–0.20)

0≤0.351.4

Missense OE?0.95 (0.90–1.01)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 5 / 53.8Missense obs/exp: 932 / 978.0Syn Z: -2.02

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveGLI3-related Pallister-Hall syndromeDNAD

definitiveGLI3-related Greig cephalopolysyndactyly syndromeLOFAD

This gene — mechanism propensity

0.3892th %ile

GOF

0.2198th %ile

LOF

0.83top 5%

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.

LOFprediction above median · 1 literature citation · 89% of P/LP variants are LoF · LOEUF 0.20 · ClinGen HI: Sufficient evidence for dosage pathogenicity

DN1 literature citation

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

DNGenotype/phenotype correlations have led to fine mapping of GLI3 and the recognition that PHS is caused by dominant negative mutations in the middle third of the gene.1

LOFGCPS is known to be caused by mutations in the transcription factor GLI3 gene (7p13) which results in functional haploinsufficiency of this gene.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

1524 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic148

Likely Pathogenic64

VUS615

Likely Benign391

Benign148

Conflicting146

148

Pathogenic

Likely Pathogenic

615

VUS

391

Likely Benign

148

Benign

146

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	136	3	9	0	148
Likely Pathogenic	52	8	4	0	64
VUS	4	531	65	15	615
Likely Benign	0	118	88	185	391
Benign	1	24	75	48	148
Conflicting	—				146
Total	193	684	241	248	1,512

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

View in ClinVar →

32 pathogenic / likely-pathogenic (of 40) ClinVar copy-number / structural variants overlap GLI3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →