Is FOXI3 p.Pro15Ser (c.43C>T) pathogenic?

FOXI3 p.Pro15Ser (c.43C>T) is classified Uncertain significance in FOXI3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-22). AlphaMissense: likely benign (0.0695); Ultra-rare (popmax 0.0159%, amr).

How common is FOXI3 p.Pro15Ser (c.43C>T) in the general population?

FOXI3 p.Pro15Ser (c.43C>T) is ultra-rare (popmax 0.0159%, amr) (gnomAD).

What do computational predictors say about FOXI3 p.Pro15Ser (c.43C>T)?

AlphaMissense predicts likely benign (score 0.0695) — an in-silico prediction, not a clinical call.

FOXI3 p.Pro15Ser

c.43C>T · rs1298246013 · VCV3019833

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0695 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0159%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.0695	likely benign
SaProt	LLR -7.88	tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP -1.1, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 563 bp · p 0.17 · regional, not allelic
Overall
CADD	17.16	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0159% Admixed American · 3/18,886 alleles

Filtering AF 0.0043% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00226%

Overall 0.000738% 8/1,083,754 alleles · ultra-rare exomes 2/935,010 · genomes 6/148,744 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0159%	6,295
African / African-American	0.00847%	11,807

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.Pro15Ser
Coding: c.43C>T
MANE Select: NM_001135649
dbSNP: rs1298246013
Type: single nucleotide variant
Location: chr2:88452493 (GRCh38)
Gene constraint: LOEUF 0.73 · pLI 0.65 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.00

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

Similar variants

FOXI3 p.Pro15Leu Uncertain significance ★ ⚠ same residue
FOXI3 p.Pro15Thr 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
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-pro15ser (accessed [today's date]).

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