FOXE3

Chr 1ADAR

forkhead box E3

Also known as: AAT11, ASGD2, CATC3, CTRCT34, FKHL12, FREAC8

NCBI Gene: 2301ENSG00000186790UniProt: Q13461

This intronless gene belongs to the forkhead family of transcription factors, which is characterized by a distinct forkhead domain. The protein encoded functions as a lens-specific transcription factor and plays an important role in vertebrate lens formation. Mutations in this gene are associated with anterior segment mesenchymal dysgenesis and congenital primary aphakia. [provided by RefSeq, Dec 2009]

Primary Disease Associations & Inheritance

{Aortic aneurysm, familial thoracic 11, susceptibility to}MIM #617349
AD
Anterior segment dysgenesis 2, multiple subtypesMIM #610256
AR
Cataract 34, multiple typesMIM #612968
AR
509
ClinVar variants
33
Pathogenic / LP
0.18
pLI score
0
Active trials
Clinical Summary— FOXE3
🧬
Gene-Disease Validity (ClinGen)
familial thoracic aortic aneurysm and aortic dissection · ADModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.18) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
33 Pathogenic / Likely Pathogenic· 353 VUS of 509 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.61LOEUF
pLI 0.181
Z-score 0.89
OE 0.40 (0.14–1.61)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.57Z-score
OE missense 0.83 (0.69–1.01)
76 obs / 91.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.40 (0.14–1.61)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.83 (0.69–1.01)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.18
0≤1.21.6
LoF obs/exp: 1 / 2.5Missense obs/exp: 76 / 91.3Syn Z: -0.95

ClinVar Variant Classifications

509 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22
Likely Pathogenic11
VUS353
Likely Benign93
Benign5
Conflicting25
22
Pathogenic
11
Likely Pathogenic
353
VUS
93
Likely Benign
5
Benign
25
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
11
3
8
0
22
Likely Pathogenic
3
5
3
0
11
VUS
6
299
17
31
353
Likely Benign
0
9
1
83
93
Benign
0
1
1
3
5
Conflicting
—25
Total2031730117509

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

View in ClinVar →

Protein Context — Lollipop Plot

FOXE3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

FOXE3-related congenital cataract

definitive
ADUndeterminedUncertain
Eye
G2P ↗

FOXE3-related congenital cataract

definitive
ARUndeterminedAltered Gene Product Structure
Eye
G2P ↗
missense variantinframe deletioninframe insertion

FOXE3-related anterior segment mesenchymal dysgenesis

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

FOXE3-related congenital primary aphakia

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
FORKHEAD BOX E3; FOXE3
MIM #601094 · *

{Aortic aneurysm, familial thoracic 11, susceptibility to}

MIM #617349

Molecular basis of disorder known

Autosomal dominant

Anterior segment dysgenesis 2, multiple subtypes

MIM #610256

Molecular basis of disorder known

Autosomal recessive

Cataract 34, multiple types

MIM #612968

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — FOXE3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
FOXE3 mutations: genotype-phenotype correlations.
Plaisancié J et al.·Clin Genet
2018Review
Mutation update of transcription factor genes FOXE3, HSF4, MAF, and PITX3 causing cataracts and other developmental ocular defects.
Anand D et al.·Hum Mutat
2018Review
Anophthalmia and microphthalmia.
Verma AS et al.·Orphanet J Rare Dis
2007Review
Congenital primary aphakia.
Ernst J et al.·J AAPOS
2022
Pathogenic variants of AIPL1, MERTK, GUCY2D, and FOXE3 in Pakistani families with clinically heterogeneous eye diseases.
Rashid M et al.·PLoS One
2020
Insights Into the FOXE3 Transcriptional Network and Disease Mechanisms From the Investigation of a Regulatory Variant Driving Complex Microphthalmia.
Plaisancié J et al.·Invest Ophthalmol Vis Sci
2025Functional
Sclerocornea-Microphthalmia-Aphakia Complex: Description of Two Additional Cases Associated With Novel FOXE3 Mutations and Review of the Literature.
Quiroz-Casian N et al.·Cornea
2018Review
Comprehensive phenotypic and functional analysis of dominant and recessive FOXE3 alleles in ocular developmental disorders.
Reis LM et al.·Hum Mol Genet
2021Functional
FOXE3 mutations predispose to thoracic aortic aneurysms and dissections.
Kuang SQ et al.·J Clin Invest
2016
Identification of novel homozygous variants in FOXE3 and AP4M1 underlying congenital syndromic anophthalmia and microphthalmia.
Akbar W et al.·J Gene Med
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools