Is FOXI3 p.Ser375Arg (c.1125C>A) pathogenic?

FOXI3 p.Ser375Arg (c.1125C>A) is classified Uncertain significance in FOXI3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-09). AlphaMissense: ambiguous (0.3455); Absent from gnomAD v4.1.

How common is FOXI3 p.Ser375Arg (c.1125C>A) in the general population?

FOXI3 p.Ser375Arg (c.1125C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FOXI3 p.Ser375Arg (c.1125C>A)?

AlphaMissense predicts ambiguous (score 0.3455) — an in-silico prediction, not a clinical call.

FOXI3 p.Ser375Arg

c.1125C>A · rs2104257845 · VCV1463995

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3455 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.3455	ambiguous
SaProt	LLR -9.52	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -1.5, phastCons 0.47
Regional constraint	o/e 0.92	unconstrained · MANE · 3,722 bp · p 0.18 · regional, not allelic
Overall
CADD	15.04	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; SaProt is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FOXI3
Protein: p.Ser375Arg
Coding: c.1125C>A
MANE Select: NM_001135649
dbSNP: rs2104257845
Type: single nucleotide variant
Location: chr2:88448345 (GRCh38)
Gene constraint: LOEUF 0.73 · pLI 0.65 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.00
Residue 375: a UniProt-annotated variant site (in cfm2; uncertain significance; decreased transcription factor activity; does not affect localization to the nucleus); the 'disordered' region

Full FOXI3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FOXI3 p.Arg236Trp Likely pathogenic ★★ same type
FOXI3 p.Ala71Pro Uncertain significance ★★ ⚠ same type
FOXI3 p.Arg238Ter Uncertain significance ★★ same type
FOXI3 p.Arg241Cys Uncertain significance ★★ ⚠ same type
FOXI3 p.Asp212Glu Uncertain significance ★★ ⚠ same type
FOXI3 p.Cys5Tyr Uncertain significance ★★ ⚠ same type
FOXI3 p.Glu163Lys Uncertain significance ★★ ⚠ same type
FOXI3 p.Gly38Ala 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/foxi3-p-ser375arg (accessed [today's date]).

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