FOXG1

Chr 14AD

forkhead box G1

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

NCBI Gene: 2290 ENSG00000176165 UniProt: P55316 OMIM: 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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This locus encodes a member of the fork-head transcription factor family. The encoded protein, which functions as a transcriptional repressor, is highly expressed in neural tissues during brain development. Mutations at this locus have been associated with Rett syndrome and a diverse spectrum of neurodevelopmental disorders defined as part of the FOXG1 syndrome. This gene is disregulated in many types of cancer and is the target of multiple microRNAs that regulate the proliferation of tumor cells. [provided by RefSeq, Jul 2020]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.331 OMIM phenotype

VCEP Guidelines: Rett/Angelman-like DisordersReleased

View Specifications ClinGen 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

285 unique Pathogenic / Likely Pathogenic· 289 VUS of 935 total submissions

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Clinical Trials

2 active or recruiting trials — 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 OE?0.00 (0.00–0.33)

0≤0.351.4

Missense OE?0.36 (0.30–0.43)

0≤0.61.4

Synonymous OE?1.29

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

This gene — mechanism propensity

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 · 60% of P/LP variants are LoF · LOEUF 0.33 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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.1

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

References

1.PMID 25565401 ↗

ClinVar Variant Classifications

935 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic174

Likely Pathogenic111

VUS289

Likely Benign267

Benign72

Conflicting22

174

Pathogenic

111

Likely Pathogenic

289

VUS

267

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	136	36	2	0	174
Likely Pathogenic	36	75	0	0	111
VUS	2	236	7	44	289
Likely Benign	0	78	8	181	267
Benign	0	45	4	23	72
Conflicting	—				22
Total	174	470	21	248	935

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

View in ClinVar →

28 pathogenic / likely-pathogenic (of 32) ClinVar copy-number / structural variants overlap FOXG1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →