Is FOXI3 p.Arg235fs (c.703dup) pathogenic?

FOXI3 p.Arg235fs (c.703dup) is classified Uncertain significance in FOXI3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01).

FOXI3 p.Arg235fs

c.703dup · VCV4724595

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (2 of 2) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: FOXI3
Protein: p.Arg235fs
Coding: c.703dup
MANE Select: NM_001135649
Type: Duplication
Location: chr2:88448766 (GRCh38)
Gene constraint: LOEUF 0.73 · pLI 0.65 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.00
Residue 235: a DNA-binding region; a UniProt-annotated variant site (in cfm2; decreased transcription factor activity; decreased 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.Arg235His Uncertain significance ★ ⚠ same residue
FOXI3 p.Arg235Cys Likely pathogenic same residue
FOXI3 p.Thr297dup Benign ★★ same type
FOXI3 p.Ala122_Ala124dup Uncertain significance ★ same type
FOXI3 p.Ala124_Gly125insAlaProAlaSerProAlaAlaProAla Uncertain significance ★ same type
FOXI3 p.Ala124_Gly125insSerProAlaAlaProAla Uncertain significance ★ same type
FOXI3 p.Ala26fs Uncertain significance ★ same type
FOXI3 p.Ala32fs Conflicting classifications of pathogenicity ★ 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-arg235fs (accessed [today's date]).

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