FOXL2

Chr 3ADAR

forkhead box L2

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

NCBI Gene: 668 ENSG00000183770 UniProt: P58012 OMIM: 605597

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]

OMIM Research

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Blepharophimosis, epicanthus inversus, and ptosis, types 1 and 2MIM #110100

ADAR

Premature ovarian failure 3MIM #608996

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Blepharophimosis, epicanthus inversus, and ptosis, types 1 and 2; Premature ovarian failure 3; no ClinGen or GenCC tier

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

191

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.44

LOEUF

LOF

Mechanism· G2P

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

Background carrier burden — how many people carry a rare variant somewhere in FOXL2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

563 rare PASS variants

Rare truncating (LoF)

1 in 9,100

27 rare PASS variants

Rare synonymous (reference)

1 in 110

343 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FOXL2. 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 140	1 in 15,000
South Asian	~43k	1 in 110	1 in 5,300
Remaining (unassigned)	~30k	1 in 120	≈ 1 in 13,000
European (Finnish)	~27k	1 in 390	≈ 1 in 7,700
Admixed American	~22k	1 in 170	1 in 3,300
African / African American	~21k	1 in 210	1 in 2,800
East Asian	~20k	1 in 220	1 in 2,200
Ashkenazi Jewish	~13k	1 in 250	1 in 1,700
Middle Eastern	~2,884	1 in 150	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): 0 of 1 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 1.? see exons ↓