FOXL2

Chr 3

forkhead box L2

Also known as: BPES, BPES1, PFRK, PINTO, POF3

NCBI Gene: 668 ENSG00000183770 UniProt: P58012

This gene encodes a forkhead transcription factor. The protein contains a fork-head DNA-binding domain and may play a role in ovarian development and function. Expansion of a polyalanine repeat region and other mutations in this gene are a cause of blepharophimosis syndrome and premature ovarian failure 3. [provided by RefSeq, Jul 2016]

GeneReviews Research

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.44

Clinical Summary— FOXL2

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.88) — some intolerance to loss-of-function variants.

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ClinVar Variants

175 unique Pathogenic / Likely Pathogenic· 90 VUS of 301 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — FOXL2

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

Moderate LoF intolerance

LoF Constraint?

0.44LOEUF

pLI 0.878

Z-score 2.42

OE 0.00 (0.00–0.44)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.76Z-score

OE missense 0.62 (0.53–0.73)

109 obs / 174.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.44)

0≤0.351.4

Missense OE?0.62 (0.53–0.73)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 0 / 6.8Missense obs/exp: 109 / 174.6Syn Z: -0.52

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveFOXL2-related blepharophimosis, ptosis, and epicanthus inversus syndromeLOFAD

This gene — mechanism propensity

0.4785th %ile

GOF

0.4085th %ile

LOF

0.79top 5%

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

LOFprediction above median · 1 literature citation · 70% of P/LP variants are LoF · LOEUF 0.44 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFFunctional Analysis of a Novel FOXL2 Indel Mutation in Chinese Families with Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome Type I1

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 28924383 ↗

ClinVar Variant Classifications

301 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic128

Likely Pathogenic47

VUS90

Likely Benign17

Benign15

Conflicting3

128

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	110	17	1	0	128
Likely Pathogenic	13	33	1	0	47
VUS	0	84	3	3	90
Likely Benign	0	2	2	13	17
Benign	0	2	4	9	15
Conflicting	—				3
Total	123	138	11	25	300

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

View in ClinVar →

27 pathogenic / likely-pathogenic (of 40) ClinVar copy-number / structural variants overlap FOXL2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →