Is FOXL2 p.Phe167= (c.501C>T) pathogenic?

FOXL2 p.Phe167= (c.501C>T) is classified Benign in FOXL2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-26). Common (popmax 33%, afr) — too common for a highly-penetrant pathogenic allele; Associated with blepharophimosis, ptosis, and epicanthus inversus syndrome.

What condition is associated with FOXL2 p.Phe167= (c.501C>T)?

FOXL2 p.Phe167= (c.501C>T) is associated with blepharophimosis, ptosis, and epicanthus inversus syndrome (ClinVar).

FOXL2 p.Phe167=

Q: How common is FOXL2 p.Phe167= (c.501C>T) in the general population?

FOXL2 p.Phe167= (c.501C>T) is common (popmax 33%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.501C>T · rs61750361 · VCV261661

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 33%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

blepharophimosis, ptosis, and epicanthus inversus syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.13	GERP -2, phastCons 0.82
Overall
CADD	11.28	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 33% African / African-American · 23,660/71,642 alleles

Filtering AF 32.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 32.5%

Overall 4.08% 62,747/1,537,794 alleles · common exomes 45,616/1,386,086 · genomes 17,131/151,708 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	33%	3
South Asian	8.79%	11
Middle Eastern	7.45%	13
East Asian	6.23%	16
Finnishnot grpmax-eligible	5.59%	18
Remaining individualsnot grpmax-eligible	4.83%	21
Admixed American	3.59%	28
Amishnot grpmax-eligible	2.86%	35
Ashkenazi Jewishnot grpmax-eligible	2.44%	41
European (non-Finnish)	1.79%	56

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: FOXL2
Protein: p.Phe167=
Coding: c.501C>T
MANE Select: NM_023067
dbSNP: rs61750361
Type: single nucleotide variant
Location: chr3:138946222 (GRCh38)
Gene constraint: LOEUF 1.913 · pLI 0.03 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.89 · 2 PDB

Full FOXL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

blepharophimosis, ptosis, and epicanthus inversus syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FOXL2 p.Phe167Ser Uncertain significance ★ ⚠ same residue
FOXL2 p.Arg349Gly Likely pathogenic ★★ ⚠ same condition
FOXL2 p.Gln196Ter Pathogenic ★★ same condition
FOXL2 p.Gln219Ter Pathogenic ★★ same condition
FOXL2 p.Leu75Phe Pathogenic ★★ same condition
FOXL2 p.Met65Ile Likely pathogenic ★★ same condition
FOXL2 p.Met65Val Pathogenic/Likely pathogenic ★★ same condition
FOXL2 p.Ser107Gly Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/foxl2-p-phe167 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown