Is FOXA2 p.Ser456Phe (c.1367C>T) pathogenic?

FOXA2 p.Ser456Phe (c.1367C>T) is classified Uncertain significance in FOXA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: likely pathogenic (0.7548); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with FOXA2 p.Ser456Phe (c.1367C>T)?

FOXA2 p.Ser456Phe (c.1367C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FOXA2 p.Ser456Phe (c.1367C>T) in the general population?

FOXA2 p.Ser456Phe (c.1367C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about FOXA2 p.Ser456Phe (c.1367C>T)?

AlphaMissense predicts likely pathogenic (score 0.7548) — an in-silico prediction, not a clinical call.

FOXA2 p.Ser456Phe

c.1367C>T · VCV4258982

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7548 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7548	likely pathogenic
REVEL	0.797	moderately pathogenic-leaning
SaProt	LLR -9.12	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 1.25	unconstrained · MANE · 597 bp · p 3.9e-05 · regional, not allelic
Overall
CADD	33.0	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 S450F vs ClinVar S456F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,906 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000373% 6/1,607,474 alleles · very rare exomes 6/1,455,158 · genomes 0/152,316 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,906
European (non-Finnish)	0.000426%	234,913

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: FOXA2
Protein: p.Ser456Phe
Coding: c.1367C>T
MANE Select: NM_021784
Type: single nucleotide variant
Location: chr20:22581875 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 58.29 · 3 PDB
Residue 450 UniProt numbering: the 'transactivation domain 2' region

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-ser456phe (accessed [today's date]).

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