Is FOXA2 p.Ala100Pro (c.298G>C) pathogenic?

FOXA2 p.Ala100Pro (c.298G>C) is classified Benign/Likely benign in FOXA2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-08). AlphaMissense: likely benign (0.0987); Low-frequency (popmax 2.22%, afr).

How common is FOXA2 p.Ala100Pro (c.298G>C) in the general population?

FOXA2 p.Ala100Pro (c.298G>C) is low-frequency (popmax 2.22%, afr) (gnomAD).

What do computational predictors say about FOXA2 p.Ala100Pro (c.298G>C)?

AlphaMissense predicts likely benign (score 0.0987) — an in-silico prediction, not a clinical call.

FOXA2 p.Ala100Pro

c.298G>C · rs201350646 · VCV1166363

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0987 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.22%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0987	likely benign
REVEL	0.304	indeterminate
SaProt	LLR -7.26	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 2.1	GERP 0.88, phastCons 0.97
Regional constraint	o/e 1.21	unconstrained · MANE · 1,528 bp · p 0.00098 · regional, not allelic
Overall
CADD	21.8	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 A94P vs ClinVar A100P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.22% African / African-American · 1,604/72,236 alleles

Filtering AF 2.13% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.09%

Overall 0.112% 1,755/1,562,556 alleles · low-frequency exomes 781/1,410,400 · genomes 974/152,156 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.22%	45
Admixed American	0.136%	733
Remaining individualsnot grpmax-eligible	0.111%	902
Middle Eastern	0.018%	5,560
European (non-Finnish)	0.000862%	115,968

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.Ala100Pro
Coding: c.298G>C
MANE Select: NM_021784
dbSNP: rs201350646
Type: single nucleotide variant
Location: chr20:22582944 (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.Ala103= 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-ala100pro (accessed [today's date]).

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