Is FOXL2 p.Ser33Arg (c.99C>A) pathogenic?

FOXL2 p.Ser33Arg (c.99C>A) is classified Uncertain significance in FOXL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-01). AlphaMissense: likely benign (0.3153); Ultra-rare (popmax 0.0166%, sas); Associated with Inborn genetic diseases.

What condition is associated with FOXL2 p.Ser33Arg (c.99C>A)?

FOXL2 p.Ser33Arg (c.99C>A) is associated with Inborn genetic diseases (ClinVar).

How common is FOXL2 p.Ser33Arg (c.99C>A) in the general population?

FOXL2 p.Ser33Arg (c.99C>A) is ultra-rare (popmax 0.0166%, sas) (gnomAD).

What do computational predictors say about FOXL2 p.Ser33Arg (c.99C>A)?

AlphaMissense predicts likely benign (score 0.3153) — an in-silico prediction, not a clinical call.

FOXL2 p.Ser33Arg

c.99C>A · rs569790915 · VCV2331606

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3153 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3153	likely benign
REVEL	0.248	benign-leaning
SaProt	LLR -8.00	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -0.036, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 159 bp · p 0.11 · regional, not allelic
Overall
CADD	16.89	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% South Asian · 15/90,576 alleles

Filtering AF 0.0101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00825%

Overall 0.001% 16/1,598,096 alleles · ultra-rare exomes 16/1,446,024 · genomes 0/152,072 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0166%	6,038
Remaining individualsnot grpmax-eligible	0.00162%	61,802

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.Ser33Arg
Coding: c.99C>A
MANE Select: NM_023067
dbSNP: rs569790915
Type: single nucleotide variant
Location: chr3:138946624 (GRCh38)
Gene constraint: LOEUF 1.913 · pLI 0.03 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.89 · 2 PDB
Residue 33: the 'disordered' region; a modified residue (phosphoserine)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FOXL2 p.Ala71Pro Uncertain significance ★★ ⚠ same condition
FOXL2 p.Met264Thr Uncertain significance ★★ ⚠ same condition
FOXL2 p.Pro212Ala Uncertain significance ★★ ⚠ same condition
FOXL2 p.Pro268Thr Uncertain significance ★★ ⚠ same condition
FOXL2 p.Ser78Tyr Uncertain significance ★★ ⚠ same condition
FOXL2 p.Ala14Pro Uncertain significance ★ ⚠ same condition
FOXL2 p.Ala183Thr Uncertain significance ★ ⚠ same condition
FOXL2 p.Ala190Thr Uncertain significance ★ ⚠ 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-ser33arg (accessed [today's date]).

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