Is FOXA2 p.Pro200Ala (c.598C>G) pathogenic?

FOXA2 p.Pro200Ala (c.598C>G) is classified Uncertain significance in FOXA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-02). AlphaMissense: likely pathogenic (0.9916); Absent from gnomAD v4.1.

How common is FOXA2 p.Pro200Ala (c.598C>G) in the general population?

FOXA2 p.Pro200Ala (c.598C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FOXA2 p.Pro200Ala (c.598C>G)?

AlphaMissense predicts likely pathogenic (score 0.9916) — an in-silico prediction, not a clinical call.

FOXA2 p.Pro200Ala

c.598C>G · rs2514813129 · VCV2163375

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9916 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9916	likely pathogenic
REVEL	0.879	moderately pathogenic-leaning
SaProt	LLR -13.24	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 139 bp · p 0.00028 · regional, not allelic
Overall
CADD	33.0	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 P194A vs ClinVar P200A) — 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.Pro200Ala
Coding: c.598C>G
MANE Select: NM_021784
dbSNP: rs2514813129
Type: single nucleotide variant
Location: chr20:22582644 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 58.29 · 3 PDB
Residue 194 UniProt numbering: a DNA-binding region; an α-helix

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-pro200ala (accessed [today's date]).

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