FOXG1

Chr 14AD

forkhead box G1

Also known as: BF1, BF2, FHKL3, FKH2, FKHL1, FKHL2, FKHL3, FKHL4

NCBI Gene: 2290ENSG00000176165UniProt: P55316OMIM: 164874

This gene encodes a transcriptional repressor that is critical for telencephalon development and establishing regional brain subdivisions during embryogenesis. Mutations cause FOXG1 syndrome, which includes congenital variant Rett syndrome and a broad spectrum of neurodevelopmental disorders, inherited in an autosomal dominant pattern. The gene is highly intolerant to loss-of-function variants, and disease predominantly results from haploinsufficiency mechanisms.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
LOFmechanismADLOEUF 0.331 OMIM phenotype
VCEP Guidelines: Rett/Angelman-like DisordersReleased
View SpecificationsClinGen Panel
Clinical Summary— FOXG1
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Gene-Disease Validity (ClinGen)
FOXG1 disorder · 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 0.94). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
78 unique Pathogenic / Likely Pathogenic· 170 VUS of 400 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — FOXG1
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint
0.33LOEUF
pLI 0.944
Z-score 2.79
OE 0.00 (0.00–0.33)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
3.49Z-score
OE missense 0.36 (0.30–0.43)
84 obs / 234.3 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios
LoF OE0.00 (0.00–0.33)
0≤0.351.4
Missense OE0.36 (0.30–0.43)
0≤0.61.4
Synonymous OE1.29
0≤1.21.6
LoF obs/exp: 0 / 9.1Missense obs/exp: 84 / 234.3Syn Z: -2.38
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveFOXG1-related congenital variant of Rett syndromeLOFAD
DN
0.2698th %ile
GOF
0.2497th %ile
LOF
0.92top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 51% of P/LP variants are LoF · LOEUF 0.33

Literature Evidence

LOFThe aim of this article is to report on the spectrum of movement disorders associated with FOXG1 haploinsufficiency, as described in the literature.PMID:25565401

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

400 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic45
Likely Pathogenic33
VUS170
Likely Benign115
Benign28
Conflicting8
45
Pathogenic
33
Likely Pathogenic
170
VUS
115
Likely Benign
28
Benign
8
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
29
11
5
0
45
Likely Pathogenic
11
22
0
0
33
VUS
2
129
6
33
170
Likely Benign
0
27
5
83
115
Benign
0
14
2
12
28
Conflicting
—8
Total4220318128399

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

View in ClinVar →

Protein Context — Lollipop Plot

FOXG1 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients