Is FOXI3 p.Pro291= (c.873G>A) pathogenic?

FOXI3 p.Pro291= (c.873G>A) is classified Likely benign in FOXI3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-20). Very rare (popmax 0.00547%, afr).

How common is FOXI3 p.Pro291= (c.873G>A) in the general population?

FOXI3 p.Pro291= (c.873G>A) is very rare (popmax 0.00547%, afr) (gnomAD).

FOXI3 p.Pro291=

c.873G>A · VCV4753882

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00547%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -15	GERP -3.6
Overall
CADD	0.334	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00547% African / African-American · 4/73,164 alleles

Filtering AF 0.00178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00106%

Overall 0.00155% 24/1,551,588 alleles · very rare exomes 19/1,399,334 · genomes 5/152,254 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00547%	18,291
South Asian	0.00238%	42,027
Remaining individualsnot grpmax-eligible	0.00166%	60,114
European (non-Finnish)	0.00148%	67,470

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.Pro291=
Coding: c.873G>A
MANE Select: NM_001135649
Type: single nucleotide variant
Location: chr2:88448597 (GRCh38)
Gene constraint: LOEUF 0.73 · pLI 0.65 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.00
Residue 291: the 'disordered' region

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

Similar variants

FOXI3 p.Pro291Leu Uncertain significance ★★ ⚠ same residue
FOXI3 p.Pro291Arg Uncertain significance ★ ⚠ same residue
FOXI3 p.Pro291Ser Uncertain significance ★ ⚠ 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

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-pro291 (accessed [today's date]).

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