Is FOXI3 p.Pro355Ser (c.1063C>T) pathogenic?

FOXI3 p.Pro355Ser (c.1063C>T) is classified Uncertain significance in FOXI3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-24). AlphaMissense: likely benign (0.0613); Very rare (popmax 8.72e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FOXI3 p.Pro355Ser (c.1063C>T)?

FOXI3 p.Pro355Ser (c.1063C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FOXI3 p.Pro355Ser (c.1063C>T) in the general population?

FOXI3 p.Pro355Ser (c.1063C>T) is very rare (popmax 8.72e-05%, nfe) (gnomAD).

What do computational predictors say about FOXI3 p.Pro355Ser (c.1063C>T)?

AlphaMissense predicts likely benign (score 0.0613) — an in-silico prediction, not a clinical call.

FOXI3 p.Pro355Ser

c.1063C>T · rs2528909402 · VCV2358498

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0613 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.72e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0613	likely benign
SaProt	LLR -5.69	tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.9	GERP -3.4
Regional constraint	o/e 0.92	unconstrained · MANE · 3,722 bp · p 0.18 · regional, not allelic
Overall
CADD	0.022	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; SaProt is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.72e-05% European (non-Finnish) · 1/1,146,980 alleles

Overall 6.44e-05% 1/1,551,708 alleles · very rare exomes 1/1,399,410 · genomes 0/152,298 · joint denominator

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: FOXI3
Protein: p.Pro355Ser
Coding: c.1063C>T
MANE Select: NM_001135649
dbSNP: rs2528909402
Type: single nucleotide variant
Location: chr2:88448407 (GRCh38)
Gene constraint: LOEUF 0.73 · pLI 0.65 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.00
Residue 355: a UniProt-annotated variant site (in cfm2; decreased transcription factor activity; does not affect localization to the nucleus)

Full FOXI3 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

FOXI3 p.Pro355Leu Uncertain significance ★ ⚠ same residue
FOXI3 p.Pro355= Likely benign ★ same residue
FOXI3 p.Ala71Pro Uncertain significance ★★ ⚠ same condition
FOXI3 p.Cys5Tyr Uncertain significance ★★ ⚠ same condition
FOXI3 p.Gly38Ala Uncertain significance ★★ ⚠ same condition
FOXI3 p.Gly38Val Uncertain significance ★★ ⚠ same condition
FOXI3 p.Leu3Phe Uncertain significance ★★ ⚠ same condition
FOXI3 p.Pro31Arg 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/foxi3-p-pro355ser (accessed [today's date]).

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