Is FOXL2 p.Ser263Arg (c.789C>A) pathogenic?

FOXL2 p.Ser263Arg (c.789C>A) is classified Likely pathogenic in FOXL2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-01). AlphaMissense: likely pathogenic (0.8901); Very rare (popmax 0.00314%, amr); Associated with Genetic non-acquired premature ovarian failure.

What condition is associated with FOXL2 p.Ser263Arg (c.789C>A)?

FOXL2 p.Ser263Arg (c.789C>A) is associated with Genetic non-acquired premature ovarian failure (ClinVar).

How common is FOXL2 p.Ser263Arg (c.789C>A) in the general population?

FOXL2 p.Ser263Arg (c.789C>A) is very rare (popmax 0.00314%, amr) (gnomAD).

What do computational predictors say about FOXL2 p.Ser263Arg (c.789C>A)?

AlphaMissense predicts likely pathogenic (score 0.8901) — an in-silico prediction, not a clinical call.

FOXL2 p.Ser263Arg

c.789C>A · rs2107743526 · VCV1255995

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8901 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00314%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Genetic non-acquired premature ovarian failure

Computational evidence

Protein change
AlphaMissense	0.8901	likely pathogenic ✓ concordant with ClinVar
REVEL	0.492	indeterminate
SaProt	LLR -6.69	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 3.1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 540 bp · p 0.57 · regional, not allelic
Overall
CADD	23.8	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

Grpmax group 0.00314% Admixed American · 1/31,818 alleles

Overall 7.27e-05% 1/1,375,268 alleles · very rare exomes 1/1,223,836 · genomes 0/151,432 · joint denominator

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.Ser263Arg
Coding: c.789C>A
MANE Select: NM_023067
dbSNP: rs2107743526
Type: single nucleotide variant
Location: chr3:138945934 (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

Genetic non-acquired premature ovarian failure — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FOXL2 p.Gly185Arg Likely pathogenic ⚠ same condition
FOXL2 p.His291fs Pathogenic same condition
FOXL2 p.Arg349Gly Likely pathogenic ★★ ⚠ same type
FOXL2 p.Gln196Ter Pathogenic ★★ same type
FOXL2 p.Gln219Ter Pathogenic ★★ same type
FOXL2 p.Leu75Phe Pathogenic ★★ same type
FOXL2 p.Met65Ile Likely pathogenic ★★ same type
FOXL2 p.Met65Val Pathogenic/Likely pathogenic ★★ same type

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-ser263arg (accessed [today's date]).

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