Is FOXA2 p.Ala335Pro (c.1003G>C) pathogenic?

FOXA2 p.Ala335Pro (c.1003G>C) is classified Likely benign in FOXA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-06). AlphaMissense: likely benign (0.0855); Ultra-rare (popmax 0.0917%, eas).

How common is FOXA2 p.Ala335Pro (c.1003G>C) in the general population?

FOXA2 p.Ala335Pro (c.1003G>C) is ultra-rare (popmax 0.0917%, eas) (gnomAD).

What do computational predictors say about FOXA2 p.Ala335Pro (c.1003G>C)?

AlphaMissense predicts likely benign (score 0.0855) — an in-silico prediction, not a clinical call.

FOXA2 p.Ala335Pro

c.1003G>C · VCV4753295

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0855 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0917%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0855	likely benign
REVEL	0.128	moderately benign-leaning
SaProt	LLR -6.52	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 1.8	GERP 0.26, phastCons 0.93
Regional constraint	o/e 1.25	unconstrained · MANE · 597 bp · p 3.9e-05 · regional, not allelic
Overall
CADD	12.05	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 A329P vs ClinVar A335P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0917% East Asian · 36/39,238 alleles

Filtering AF 0.068% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0599%

Overall 0.00264% 39/1,475,808 alleles · ultra-rare exomes 30/1,323,586 · genomes 9/152,222 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0917%	1,090
Remaining individualsnot grpmax-eligible	0.00353%	28,362
European (non-Finnish)	8.93e-05%	1,119,370

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.Ala335Pro
Coding: c.1003G>C
MANE Select: NM_021784
Type: single nucleotide variant
Location: chr20:22582239 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 58.29 · 3 PDB
Residue 329 UniProt numbering: the 'disordered' region

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

Similar variants

FOXA2 p.Ala335Gly Benign ★ same residue
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

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-ala335pro (accessed [today's date]).

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