Is FOXE1 p.Arg222Pro (c.665G>C) pathogenic?

FOXE1 p.Arg222Pro (c.665G>C) is classified Uncertain significance in FOXE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-15). AlphaMissense: likely benign (0.1754); Ultra-rare (popmax 0.0143%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FOXE1 p.Arg222Pro (c.665G>C)?

FOXE1 p.Arg222Pro (c.665G>C) is associated with Inborn genetic diseases (ClinVar).

How common is FOXE1 p.Arg222Pro (c.665G>C) in the general population?

FOXE1 p.Arg222Pro (c.665G>C) is ultra-rare (popmax 0.0143%, nfe) (gnomAD).

What do computational predictors say about FOXE1 p.Arg222Pro (c.665G>C)?

AlphaMissense predicts likely benign (score 0.1754) — an in-silico prediction, not a clinical call.

FOXE1 p.Arg222Pro

c.665G>C · VCV4026294

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1754 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1754	likely benign
REVEL	0.425	indeterminate
SaProt	LLR -5.43	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP -1.2, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 555 bp · p 0.1 · regional, not allelic
Overall
CADD	24.1	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0143% European (non-Finnish) · 151/1,052,316 alleles

Filtering AF 0.0125% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0118%

Overall 0.0126% 169/1,339,684 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0339%	2,952
European (non-Finnish)grpmax	0.0143%	6,969
Admixed American	0.00379%	26,380

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg222Pro
Coding: c.665G>C
MANE Select: NM_004473
Type: single nucleotide variant
Location: chr9:97854579 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FOXE1 p.Ala118Val Uncertain significance ★★ ⚠ same condition
FOXE1 p.Ala206Thr Uncertain significance ★★ ⚠ same condition
FOXE1 p.Arg51Gly Uncertain significance ★★ ⚠ same condition
FOXE1 p.Gly334Ala Uncertain significance ★★ ⚠ same condition
FOXE1 p.Leu205Val Uncertain significance ★★ ⚠ same condition
FOXE1 p.Ala159Thr Uncertain significance ★ ⚠ same condition
FOXE1 p.Ala164Val Uncertain significance ★ ⚠ same condition
FOXE1 p.Ala171Thr 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/foxe1-p-arg222pro (accessed [today's date]).

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