Is FOXA2 p.Ser138Phe (c.413C>T) pathogenic?

FOXA2 p.Ser138Phe (c.413C>T) is classified Uncertain significance in FOXA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-29). AlphaMissense: ambiguous (0.4386); Absent from gnomAD v4.1.

How common is FOXA2 p.Ser138Phe (c.413C>T) in the general population?

FOXA2 p.Ser138Phe (c.413C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FOXA2 p.Ser138Phe (c.413C>T)?

AlphaMissense predicts ambiguous (score 0.4386) — an in-silico prediction, not a clinical call.

FOXA2 p.Ser138Phe

c.413C>T · VCV4774960

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4386 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4386	ambiguous
REVEL	0.137	moderately benign-leaning
SaProt	LLR -10.85	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 0.36, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 1,528 bp · p 0.00098 · regional, not allelic
Overall
CADD	28.5	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S132F vs ClinVar S138F) — 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.Ser138Phe
Coding: c.413C>T
MANE Select: NM_021784
Type: single nucleotide variant
Location: chr20:22582829 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 58.29 · 3 PDB

Full FOXA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FOXA2 p.Ala92Val Uncertain significance ★★ ⚠ same type
FOXA2 p.Glu373Asp Uncertain significance ★★ ⚠ same type
FOXA2 p.Met108Ile Uncertain significance ★★ ⚠ same type
FOXA2 p.Met52Thr Uncertain significance ★★ same type
FOXA2 p.Pro358Gln Uncertain significance ★★ ⚠ same type
FOXA2 p.Ser99Leu Uncertain significance ★★ ⚠ same type
FOXA2 c.*6C>T Likely benign ★★ same type
FOXA2 p.Ala100Pro Benign/Likely benign ★★ 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/foxa2-p-ser138phe (accessed [today's date]).

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