Is FOXA2 p.Ala351= (c.1053C>G) pathogenic?

FOXA2 p.Ala351= (c.1053C>G) is classified Likely benign in FOXA2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-04-05). Rare (popmax 0.367%, sas); Associated with FOXA2-related disorder.

What condition is associated with FOXA2 p.Ala351= (c.1053C>G)?

FOXA2 p.Ala351= (c.1053C>G) is associated with FOXA2-related disorder (ClinVar).

How common is FOXA2 p.Ala351= (c.1053C>G) in the general population?

FOXA2 p.Ala351= (c.1053C>G) is rare (popmax 0.367%, sas) (gnomAD).

FOXA2 p.Ala351=

c.1053C>G · rs562230926 · VCV3048214

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.367%, sas)

Conditions

FOXA2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.55	GERP -4.5, phastCons 0.004
Overall
CADD	7.204	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.367% South Asian · 310/84,466 alleles

Filtering AF 0.333% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.32%

Overall 0.0213% 330/1,551,538 alleles · rare exomes 310/1,399,234 · genomes 20/152,304 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.367%	272
Remaining individualsnot grpmax-eligible	0.025%	4,003
African / African-American	0.00546%	18,310
European (non-Finnish)	8.72e-05%	1,146,811

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.Ala351=
Coding: c.1053C>G
MANE Select: NM_021784
dbSNP: rs562230926
Type: single nucleotide variant
Location: chr20:22582189 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 58.29 · 3 PDB
Residue 351: the 'disordered' region

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

Disease context

FOXA2-related disorder

Similar variants

FOXA2 p.Ala351Asp Uncertain significance ★ ⚠ same residue
FOXA2 p.Ser169Trp Likely pathogenic ★ same condition
FOXA2 p.Leu41Val Uncertain significance ★ ⚠ same condition
FOXA2 p.Gly453Glu Uncertain significance ⚠ same condition
FOXA2 p.Gly121= Likely benign same condition
FOXA2 p.Gln122fs Uncertain significance ★ same condition
FOXA2 p.Ala92Val Uncertain significance ★★ ⚠ same type
FOXA2 p.Glu373Asp Uncertain significance ★★ ⚠ 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-ala351 (accessed [today's date]).

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