Is FOXL2 p.Ser217Phe (c.650C>T) pathogenic?

FOXL2 p.Ser217Phe (c.650C>T) is classified Pathogenic/Likely pathogenic in FOXL2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2023-10-23). AlphaMissense: likely pathogenic (0.8421); No allele count reported in gnomAD v4.1 (AN 1,420,356); Associated with FOXL2-related disorders.

What condition is associated with FOXL2 p.Ser217Phe (c.650C>T)?

FOXL2 p.Ser217Phe (c.650C>T) is associated with FOXL2-related disorders, blepharophimosis, ptosis, and epicanthus inversus syndrome (ClinVar).

How common is FOXL2 p.Ser217Phe (c.650C>T) in the general population?

FOXL2 p.Ser217Phe (c.650C>T) is no allele count reported in gnomAD v4.1 (AN 1,420,356) (gnomAD).

What do computational predictors say about FOXL2 p.Ser217Phe (c.650C>T)?

AlphaMissense predicts likely pathogenic (score 0.8421) — an in-silico prediction, not a clinical call.

FOXL2 p.Ser217Phe

c.650C>T · rs797044527 · VCV180594

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.8421 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,420,356)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

FOXL2-related disorders

Computational evidence

Protein change
AlphaMissense	0.8421	likely pathogenic ✓ concordant with ClinVar
REVEL	0.766	pathogenic-leaning
SaProt	LLR -10.83	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 540 bp · p 0.57 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,420,356). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: FOXL2
Protein: p.Ser217Phe
Coding: c.650C>T
MANE Select: NM_023067
dbSNP: rs797044527
Type: single nucleotide variant
Location: chr3:138946073 (GRCh38)
Gene constraint: LOEUF 1.913 · pLI 0.03 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.89 · 2 PDB
Residue 217: a UniProt-annotated variant site (in bpes; diffuse nuclear localization; normal transcriptional activation); a UniProt-annotated variant site (in bpes; diffuse nuclear localization; increased transactivation activity)

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

Disease context

FOXL2-related disorders

Also linked: blepharophimosis, ptosis, and epicanthus inversus syndrome

Similar variants

FOXL2 p.Ser217Cys Pathogenic ★ same residue
FOXL2 p.Ser217= Benign ★ 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

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-ser217phe (accessed [today's date]).

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