Is FOXI3 p.Ser299fs (c.894dup) pathogenic?

FOXI3 p.Ser299fs (c.894dup) is classified Uncertain significance in FOXI3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-30). Very rare (popmax 6.45e-05%).

How common is FOXI3 p.Ser299fs (c.894dup) in the general population?

FOXI3 p.Ser299fs (c.894dup) is very rare (popmax 6.45e-05%) (gnomAD).

FOXI3 p.Ser299fs

c.894dup · VCV3724277

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 6.45e-05%)

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 5.3	GERP 0.75, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.45e-05%

Overall 6.45e-05% 1/1,551,466 alleles · very rare exomes 1/1,399,286 · genomes 0/152,180 · 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.Ser299fs
Coding: c.894dup
MANE Select: NM_001135649
Type: Duplication
Location: chr2:88448575 (GRCh38)
Gene constraint: LOEUF 0.73 · pLI 0.65 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.00
Residue 299: the 'disordered' region

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

Similar variants

FOXI3 p.Ser299Leu Likely benign ★ 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
FOXI3 p.Ala74_Tyr75insAlaAlaAlaAlaAla 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-ser299fs (accessed [today's date]).

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