Is FOXA2 p.His416Pro (c.1247A>C) pathogenic?

FOXA2 p.His416Pro (c.1247A>C) is classified Conflicting classifications of pathogenicity in FOXA2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-05-19). AlphaMissense: likely benign (0.1098); Ultra-rare (popmax 0.055%, amr); Associated with Inborn genetic diseases.

What condition is associated with FOXA2 p.His416Pro (c.1247A>C)?

FOXA2 p.His416Pro (c.1247A>C) is associated with Inborn genetic diseases (ClinVar).

How common is FOXA2 p.His416Pro (c.1247A>C) in the general population?

FOXA2 p.His416Pro (c.1247A>C) is ultra-rare (popmax 0.055%, amr) (gnomAD).

What do computational predictors say about FOXA2 p.His416Pro (c.1247A>C)?

AlphaMissense predicts likely benign (score 0.1098) — an in-silico prediction, not a clinical call.

FOXA2 p.His416Pro

c.1247A>C · rs186945948 · VCV2299558

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1098 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.055%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1098	likely benign
REVEL	0.181	moderately benign-leaning
SaProt	LLR -5.29	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 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 1.25	unconstrained · MANE · 597 bp · p 3.9e-05 · regional, not allelic
Overall
CADD	25.2	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 H410P vs ClinVar H416P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.055% Admixed American · 33/60,024 alleles

Filtering AF 0.0402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0351%

Overall 0.00211% 34/1,614,186 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.055%	1,819
Remaining individualsnot grpmax-eligible	0.0016%	62,508

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.His416Pro
Coding: c.1247A>C
MANE Select: NM_021784
dbSNP: rs186945948
Type: single nucleotide variant
Location: chr20:22581995 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 58.29 · 3 PDB
Residue 416: the 'transactivation domain 2' 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.Pro358Gln 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

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-his416pro (accessed [today's date]).

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