Is FOXA2 p.Pro227Ser (c.679C>T) pathogenic?

FOXA2 p.Pro227Ser (c.679C>T) is classified Uncertain significance in FOXA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-21). AlphaMissense: likely pathogenic (0.8093); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with FOXA2 p.Pro227Ser (c.679C>T)?

FOXA2 p.Pro227Ser (c.679C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FOXA2 p.Pro227Ser (c.679C>T) in the general population?

FOXA2 p.Pro227Ser (c.679C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FOXA2 p.Pro227Ser (c.679C>T)?

AlphaMissense predicts likely pathogenic (score 0.8093) — an in-silico prediction, not a clinical call.

FOXA2 p.Pro227Ser

c.679C>T · VCV4839495

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8093 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8093	likely pathogenic
REVEL	0.789	moderately pathogenic-leaning
SaProt	LLR -13.02	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 8.6	GERP -3.8, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 115 bp · p 4.6e-05 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

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

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P221S vs ClinVar P227S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FOXA2
Protein: p.Pro227Ser
Coding: c.679C>T
MANE Select: NM_021784
Type: single nucleotide variant
Location: chr20:22582563 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 58.29 · 3 PDB
Residue 221 UniProt numbering: a DNA-binding region; an α-helix

Full FOXA2 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

FOXA2 p.Ala92Val Uncertain significance ★★ ⚠ same condition
FOXA2 p.Glu373Asp Uncertain significance ★★ ⚠ same condition
FOXA2 p.Met108Ile Uncertain significance ★★ ⚠ same condition
FOXA2 p.Met52Thr Uncertain significance ★★ same condition
FOXA2 p.Pro358Gln Uncertain significance ★★ ⚠ same condition
FOXA2 p.Ser99Leu Uncertain significance ★★ ⚠ same condition
FOXA2 p.Ala102Glu Uncertain significance ★ ⚠ same condition
FOXA2 p.Ala106Glu 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/foxa2-p-pro227ser (accessed [today's date]).

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