Is FOXE3 p.Ser263Pro (c.787T>C) pathogenic?

FOXE3 p.Ser263Pro (c.787T>C) is classified Likely benign in FOXE3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-26). AlphaMissense: likely benign (0.0895); Very rare (popmax 0.00196%, nfe).

How common is FOXE3 p.Ser263Pro (c.787T>C) in the general population?

FOXE3 p.Ser263Pro (c.787T>C) is very rare (popmax 0.00196%, nfe) (gnomAD).

What do computational predictors say about FOXE3 p.Ser263Pro (c.787T>C)?

AlphaMissense predicts likely benign (score 0.0895) — an in-silico prediction, not a clinical call.

FOXE3 p.Ser263Pro

c.787T>C · VCV4973528

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0895 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00196%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0895	likely benign
REVEL	0.164	moderately benign-leaning
SaProt	LLR -4.91	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 -2.3	GERP -3.6
Regional constraint	o/e 1.02	unconstrained · MANE · 956 bp · p 0.59 · regional, not allelic
Overall
CADD	3.351	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00196% European (non-Finnish) · 21/1,071,844 alleles

Filtering AF 0.00126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00107%

Overall 0.00158% 22/1,392,784 alleles · very rare exomes 22/1,242,922 · genomes 0/149,862 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00196%	51,040
Remaining individualsnot grpmax-eligible	0.00192%	52,184

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: FOXE3
Protein: p.Ser263Pro
Coding: c.787T>C
MANE Select: NM_012186
Type: single nucleotide variant
Location: chr1:47417102 (GRCh38)
Gene constraint: LOEUF 1.935 · pLI 0.12 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 66.68

Full FOXE3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FOXE3 p.Ser263= Likely benign ★ same residue
FOXE3 p.Ala78Thr Pathogenic/Likely pathogenic ★★ same type
FOXE3 p.Cys240Ter Pathogenic ★★ same type
FOXE3 p.Gly49Ter Pathogenic/Likely pathogenic ★★ same type
FOXE3 p.Ser211Ter Pathogenic/Likely pathogenic ★★ same type
FOXE3 p.Ala170Thr Uncertain significance ★★ ⚠ same type
FOXE3 p.Ala189Val Uncertain significance ★★ ⚠ same type
FOXE3 p.Ala206Asp 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/foxe3-p-ser263pro (accessed [today's date]).

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