Is FOXA2 p.Pro358Gln (c.1073C>A) pathogenic?

FOXA2 p.Pro358Gln (c.1073C>A) is classified Uncertain significance in FOXA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-13). AlphaMissense: likely benign (0.0823); Ultra-rare (popmax 0.0598%, afr); Associated with Inborn genetic diseases.

What condition is associated with FOXA2 p.Pro358Gln (c.1073C>A)?

FOXA2 p.Pro358Gln (c.1073C>A) is associated with Inborn genetic diseases (ClinVar).

How common is FOXA2 p.Pro358Gln (c.1073C>A) in the general population?

FOXA2 p.Pro358Gln (c.1073C>A) is ultra-rare (popmax 0.0598%, afr) (gnomAD).

What do computational predictors say about FOXA2 p.Pro358Gln (c.1073C>A)?

AlphaMissense predicts likely benign (score 0.0823) — an in-silico prediction, not a clinical call.

FOXA2 p.Pro358Gln

c.1073C>A · rs565350443 · VCV2217278

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0823 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0598%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0823	likely benign
REVEL	0.125	moderately benign-leaning
SaProt	LLR -6.38	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 7.5	GERP 0.17, phastCons 1
Regional constraint	o/e 1.25	unconstrained · MANE · 597 bp · p 3.9e-05 · regional, not allelic
Overall
CADD	19.5	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 P352Q vs ClinVar P358Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0598% African / African-American · 44/73,526 alleles

Filtering AF 0.0458% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0408%

Overall 0.00353% 55/1,557,846 alleles · ultra-rare exomes 30/1,405,566 · genomes 25/152,280 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0598%	1,671
Admixed American	0.00973%	10,274
Remaining individualsnot grpmax-eligible	0.00166%	60,314
European (non-Finnish)	0.000435%	230,062

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.Pro358Gln
Coding: c.1073C>A
MANE Select: NM_021784
dbSNP: rs565350443
Type: single nucleotide variant
Location: chr20:22582169 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 58.29 · 3 PDB
Residue 352 UniProt numbering: 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.Ser99Leu Uncertain significance ★★ ⚠ same condition
FOXA2 p.Ala102Glu Uncertain significance ★ ⚠ same condition
FOXA2 p.Ala106Glu Uncertain significance ★ ⚠ same condition
FOXA2 p.Ala106Thr 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-pro358gln (accessed [today's date]).

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