Is FOXI3 p.Pro31Arg (c.92C>G) pathogenic?

FOXI3 p.Pro31Arg (c.92C>G) is classified Uncertain significance in FOXI3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-13). AlphaMissense: likely benign (0.1402); Ultra-rare (popmax 0.0122%, afr); Associated with Inborn genetic diseases.

What condition is associated with FOXI3 p.Pro31Arg (c.92C>G)?

FOXI3 p.Pro31Arg (c.92C>G) is associated with Inborn genetic diseases (ClinVar).

How common is FOXI3 p.Pro31Arg (c.92C>G) in the general population?

FOXI3 p.Pro31Arg (c.92C>G) is ultra-rare (popmax 0.0122%, afr) (gnomAD).

What do computational predictors say about FOXI3 p.Pro31Arg (c.92C>G)?

AlphaMissense predicts likely benign (score 0.1402) — an in-silico prediction, not a clinical call.

FOXI3 p.Pro31Arg

c.92C>G · rs962277897 · VCV2187375

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1402 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0122%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1402	likely benign
SaProt	LLR -8.14	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 5.2	GERP -2.1, phastCons 0.98
Regional constraint	o/e 0.91	unconstrained · MANE · 563 bp · p 0.17 · regional, not allelic
Overall
CADD	16.46	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 0.0122% African / African-American · 7/57,426 alleles

Filtering AF 0.00565% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00404%

Overall 0.00144% 15/1,042,250 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0122%	8,204
Remaining individualsnot grpmax-eligible	0.00912%	10,971
European (non-Finnish)	0.000576%	173,760

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.Pro31Arg
Coding: c.92C>G
MANE Select: NM_001135649
dbSNP: rs962277897
Type: single nucleotide variant
Location: chr2:88452444 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FOXI3 p.Pro31Gln Uncertain significance ★ ⚠ same residue
FOXI3 p.Pro31Ser Uncertain significance ★ ⚠ same residue
FOXI3 p.Ala71Pro Uncertain significance ★★ ⚠ same condition
FOXI3 p.Cys5Tyr Uncertain significance ★★ ⚠ same condition
FOXI3 p.Gly38Ala Uncertain significance ★★ ⚠ same condition
FOXI3 p.Gly38Val Uncertain significance ★★ ⚠ same condition
FOXI3 p.Leu3Phe Uncertain significance ★★ ⚠ same condition
FOXI3 p.Val11Gly Uncertain significance ★★ ⚠ same condition

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-pro31arg (accessed [today's date]).

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