Is FOXE1 p.Ala282= (c.846G>A) pathogenic?

FOXE1 p.Ala282= (c.846G>A) is classified Benign in FOXE1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-05-05). Common (popmax 5.39%, afr) — too common for a highly-penetrant pathogenic allele.

FOXE1 p.Ala282=

Q: How common is FOXE1 p.Ala282= (c.846G>A) in the general population?

FOXE1 p.Ala282= (c.846G>A) is common (popmax 5.39%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.846G>A · rs142235457 · VCV167088

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 5.39%, afr) — too common for a highly-penetrant pathogenic allele

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 -2.3	GERP -3.8
Overall
CADD	5.041	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.39% African / African-American · 3,751/69,642 alleles

Filtering AF 5.24% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.18%

Overall 0.28% 4,154/1,484,240 alleles · common exomes 1,825/1,332,062 · genomes 2,329/152,178 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.39%	19
Admixed American	0.371%	270
Remaining individualsnot grpmax-eligible	0.337%	297
Middle Eastern	0.215%	466
South Asian	0.00798%	12,533
European (non-Finnish)	0.00302%	33,150
East Asian	0.00255%	39,292

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: FOXE1
Protein: p.Ala282=
Coding: c.846G>A
MANE Select: NM_004473
dbSNP: rs142235457
Type: single nucleotide variant
Location: chr9:97854760 (GRCh38)
Gene constraint: LOEUF 1.926 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 62.02

Full FOXE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FOXE1 p.Ala282Ser Uncertain significance ★ ⚠ same residue
FOXE1 p.Ala118Val Uncertain significance ★★ ⚠ same type
FOXE1 p.Ala206Thr Uncertain significance ★★ ⚠ same type
FOXE1 p.Arg51Gly Uncertain significance ★★ ⚠ same type
FOXE1 p.Gly334Ala Uncertain significance ★★ ⚠ same type
FOXE1 p.Leu205Val Uncertain significance ★★ ⚠ same type
FOXE1 p.Ser294Asn Uncertain significance ★★ ⚠ same type
FOXE1 c.-131G>C 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/foxe1-p-ala282 (accessed [today's date]).

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