Is FOXA2 p.Ala334Val (c.1001C>T) pathogenic?

FOXA2 p.Ala334Val (c.1001C>T) is classified Conflicting classifications of pathogenicity in FOXA2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-12-22). AlphaMissense: likely benign (0.1036); Rare (popmax 0.23%, eas).

How common is FOXA2 p.Ala334Val (c.1001C>T) in the general population?

FOXA2 p.Ala334Val (c.1001C>T) is rare (popmax 0.23%, eas) (gnomAD).

What do computational predictors say about FOXA2 p.Ala334Val (c.1001C>T)?

AlphaMissense predicts likely benign (score 0.1036) — an in-silico prediction, not a clinical call.

FOXA2 p.Ala334Val

c.1001C>T · rs199796119 · VCV1684750

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1036 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.23%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1036	likely benign
REVEL	0.488	indeterminate
SaProt	LLR -8.80	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 5	GERP 0.1, phastCons 0.99
Regional constraint	o/e 1.25	unconstrained · MANE · 597 bp · p 3.9e-05 · regional, not allelic
Overall
CADD	14.82	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 A328V vs ClinVar A334V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.23% East Asian · 90/39,134 alleles

Filtering AF 0.192% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.177%

Overall 0.00665% 98/1,473,698 alleles · rare exomes 82/1,321,498 · genomes 16/152,200 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.23%	435
Remaining individualsnot grpmax-eligible	0.0053%	18,878
African / African-American	0.00145%	68,900
South Asian	0.00141%	70,710
European (non-Finnish)	0.000268%	372,852

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.Ala334Val
Coding: c.1001C>T
MANE Select: NM_021784
dbSNP: rs199796119
Type: single nucleotide variant
Location: chr20:22582241 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 58.29 · 3 PDB
Residue 328 UniProt numbering: a UniProt-annotated variant site (in japanese subjects with maturity-onset diabetes of the young; uncertain significance); the 'disordered' region

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-ala334val (accessed [today's date]).

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