GLI2

Chr 2

GLI family zinc finger 2

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

NCBI Gene: 2736 ENSG00000074047 UniProt: P10070

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.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtHoloprosencephaly 9

UniProtCuller-Jones syndrome

Clinical highlights

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

130

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.31

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — GLI2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 OE?0.18 (0.11–0.31)

0≤0.351.4

Missense OE?0.93 (0.88–0.98)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

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

Background carrier burden — how many people carry a rare variant somewhere in GLI2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 25

2,250 rare PASS variants

Rare truncating (LoF)

1 in 2,600

91 rare PASS variants

Rare synonymous (reference)

1 in 37

1,033 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GLI2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 40	1 in 3,000
South Asian	~43k	1 in 22	1 in 1,700
Remaining (unassigned)	~30k	1 in 19	1 in 2,400
European (Finnish)	~27k	1 in 65	1 in 4,800
Admixed American	~22k	1 in 20	1 in 1,200
African / African American	~21k	1 in 20	1 in 2,200
East Asian	~20k	1 in 27	1 in 990
Ashkenazi Jewish	~13k	1 in 65	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 24	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 13 of 13 coding exons well covered in gnomAD exomes. Genomes: 12 of 13 (exon 5 below).? see exons ↓