GLI2

Chr 2AD

GLI family zinc finger 2

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

NCBI Gene: 2736 ENSG00000074047 UniProt: P10070 OMIM: 165230

GLI2 encodes a zinc finger transcription factor that regulates gene expression in the sonic hedgehog signaling pathway, which is essential for normal embryonic development. Mutations cause autosomal dominant conditions including Culler-Jones syndrome, holoprosencephaly 9, Greig cephalopolysyndactyly syndrome, and Pallister-Hall syndrome, affecting brain development and limb formation. The gene is highly constrained against loss-of-function variants (pLI 0.97), reflecting its critical developmental role.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

LOFmechanismADLOEUF 0.312 OMIM phenotypes

Clinical Summary— GLI2

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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.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

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

0.82Z-score

OE missense 0.93 (0.88–0.98)

896 obs / 967.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.18 (0.11–0.31)

0≤0.351.4

Missense OE0.93 (0.88–0.98)

0≤0.61.4

Synonymous OE0.96

0≤1.21.6

LoF obs/exp: 9 / 50.8Missense obs/exp: 896 / 967.5Syn Z: 0.74

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveGLI2-related holoprosencephalyLOFAD

0.3991th %ile

GOF

0.2497th %ile

LOF

0.81top 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 · LOEUF 0.31

DN1 literature citation

Literature Evidence

DNFunctional assays confirmed the pathogenicity of the identified variant and revealed a dominant-negative effect of mutant GLI2 on Hedgehog signalling.PMID:30629636

LOFDiagnostic exome sequencing identifies GLI2 haploinsufficiency and chromosome 20 uniparental disomy in a patient with developmental anomalies.PMID:29988648

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