Is FOXL2 p.Ala71Pro (c.211G>C) pathogenic?

FOXL2 p.Ala71Pro (c.211G>C) is classified Uncertain significance in FOXL2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-01-13). AlphaMissense: likely benign (0.0858); Very rare (popmax 0.00814%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FOXL2 p.Ala71Pro (c.211G>C)?

FOXL2 p.Ala71Pro (c.211G>C) is associated with Inborn genetic diseases, premature ovarian failure 3 (ClinVar).

How common is FOXL2 p.Ala71Pro (c.211G>C) in the general population?

FOXL2 p.Ala71Pro (c.211G>C) is very rare (popmax 0.00814%, nfe) (gnomAD).

What do computational predictors say about FOXL2 p.Ala71Pro (c.211G>C)?

AlphaMissense predicts likely benign (score 0.0858) — an in-silico prediction, not a clinical call.

FOXL2 p.Ala71Pro

c.211G>C · rs757571219 · VCV2255892

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0858 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00814%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0858	likely benign
REVEL	0.348	indeterminate
SaProt	LLR -3.31	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 3.1, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 283 bp · p 1.2e-10 · regional, not allelic
Overall
CADD	24.0	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 0.00814% European (non-Finnish) · 96/1,180,014 alleles

Filtering AF 0.00681% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.00607% 98/1,613,778 alleles · very rare exomes 97/1,461,542 · genomes 1/152,236 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00814%	12,292
Remaining individualsnot grpmax-eligible	0.0016%	62,480
African / African-American	0.00133%	74,950

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.Ala71Pro
Coding: c.211G>C
MANE Select: NM_023067
dbSNP: rs757571219
Type: single nucleotide variant
Location: chr3:138946512 (GRCh38)
Gene constraint: LOEUF 1.913 · pLI 0.03 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.89 · 2 PDB
Residue 71: a DNA-binding region; a β-strand

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

Also linked: premature ovarian failure 3

Similar variants

FOXL2 p.Arg349Gly Likely pathogenic ★★ ⚠ same condition
FOXL2 p.Gln219Ter Pathogenic ★★ same condition
FOXL2 p.Arg103His 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.Phe112Cys 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-ala71pro (accessed [today's date]).

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