Is FOXI3 p.Phe234Leu (c.702C>G) pathogenic?

FOXI3 p.Phe234Leu (c.702C>G) is classified Uncertain significance in FOXI3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-09). AlphaMissense: likely pathogenic (0.9999); Very rare (popmax 0.00274%, afr).

How common is FOXI3 p.Phe234Leu (c.702C>G) in the general population?

FOXI3 p.Phe234Leu (c.702C>G) is very rare (popmax 0.00274%, afr) (gnomAD).

What do computational predictors say about FOXI3 p.Phe234Leu (c.702C>G)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

FOXI3 p.Phe234Leu

c.702C>G · rs955268781 · VCV2123579

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00274%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic · top 6% in FOXI3
SaProt	LLR -12.93	damaging
⇒ AlphaMissense and SaProt both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP -1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 3,722 bp · p 0.18 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00274% African / African-American · 2/73,044 alleles

Filtering AF 0.000454% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00017%

Overall 0.000129% 2/1,551,700 alleles · very rare exomes 0/1,399,500 · genomes 2/152,200 · 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.Phe234Leu
Coding: c.702C>G
MANE Select: NM_001135649
dbSNP: rs955268781
Type: single nucleotide variant
Location: chr2:88448768 (GRCh38)
Gene constraint: LOEUF 0.73 · pLI 0.65 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.00
Residue 234: a DNA-binding region; a UniProt-annotated variant site (in cfm2; decreased transcription factor activity; does not affect localization to the nucleus); a UniProt-annotated variant site (in cfm2; decreased transcription factor activity; localization to the nucleus but aggregating into granular foci); the 'disordered' region

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

Similar variants

FOXI3 p.Phe234Val Pathogenic/Likely pathogenic same residue
FOXI3 p.Phe234fs Likely pathogenic ★ same residue
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

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-phe234leu (accessed [today's date]).

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