Is FOXA2 p.Lys280Arg (c.839A>G) pathogenic?

FOXA2 p.Lys280Arg (c.839A>G) is classified Uncertain significance in FOXA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-08). AlphaMissense: likely benign (0.0738); Ultra-rare (popmax 0.0155%, amr); Associated with Inborn genetic diseases.

What condition is associated with FOXA2 p.Lys280Arg (c.839A>G)?

FOXA2 p.Lys280Arg (c.839A>G) is associated with Inborn genetic diseases (ClinVar).

How common is FOXA2 p.Lys280Arg (c.839A>G) in the general population?

FOXA2 p.Lys280Arg (c.839A>G) is ultra-rare (popmax 0.0155%, amr) (gnomAD).

What do computational predictors say about FOXA2 p.Lys280Arg (c.839A>G)?

AlphaMissense predicts likely benign (score 0.0738) — an in-silico prediction, not a clinical call.

FOXA2 p.Lys280Arg

c.839A>G · rs1287329861 · VCV2600556

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0738 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0155%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0738	likely benign
REVEL	0.195	benign-leaning
SaProt	LLR -6.79	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 7.9	GERP 1.3, phastCons 1
Regional constraint	o/e 1.25	unconstrained · MANE · 597 bp · p 3.9e-05 · regional, not allelic
Overall
CADD	16.93	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM K274R vs ClinVar K280R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0155% Admixed American · 8/51,682 alleles

Filtering AF 0.00763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00559%

Overall 0.000959% 15/1,564,352 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0155%	6,460
Remaining individualsnot grpmax-eligible	0.00166%	60,084
European (non-Finnish)	0.000517%	193,408

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.Lys280Arg
Coding: c.839A>G
MANE Select: NM_021784
dbSNP: rs1287329861
Type: single nucleotide variant
Location: chr20:22582403 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 58.29 · 3 PDB
Residue 280: the 'disordered' 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-lys280arg (accessed [today's date]).

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