Is FOXI3 p.Pro85Ser (c.253C>T) pathogenic?

FOXI3 p.Pro85Ser (c.253C>T) is classified Conflicting classifications of pathogenicity in FOXI3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-24). AlphaMissense: likely benign (0.0758); Rare (popmax 0.438%, afr); Associated with Inborn genetic diseases.

What condition is associated with FOXI3 p.Pro85Ser (c.253C>T)?

FOXI3 p.Pro85Ser (c.253C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FOXI3 p.Pro85Ser (c.253C>T) in the general population?

FOXI3 p.Pro85Ser (c.253C>T) is rare (popmax 0.438%, afr) (gnomAD).

What do computational predictors say about FOXI3 p.Pro85Ser (c.253C>T)?

AlphaMissense predicts likely benign (score 0.0758) — an in-silico prediction, not a clinical call.

FOXI3 p.Pro85Ser

c.253C>T · rs1296112405 · VCV1585572

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0758 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.438%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0758	likely benign
SaProt	LLR -12.88	damaging
⇒ SaProt calls this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 0.78, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 563 bp · p 0.17 · regional, not allelic
Overall
CADD	17.45	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; SaProt is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.438% African / African-American · 249/56,792 alleles

Filtering AF 0.394% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.376%

Overall 0.0317% 312/983,410 alleles · rare exomes 112/837,126 · genomes 200/146,284 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.438%	228
Admixed American	0.0819%	1,221
Middle Eastern	0.0521%	1,918
Remaining individualsnot grpmax-eligible	0.0474%	2,109
Ashkenazi Jewishnot grpmax-eligible	0.0116%	8,612
European (non-Finnish)	0.0041%	24,411

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.Pro85Ser
Coding: c.253C>T
MANE Select: NM_001135649
dbSNP: rs1296112405
Type: single nucleotide variant
Location: chr2:88452283 (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.Pro85Ala Uncertain significance ★ ⚠ same residue
FOXI3 p.Pro85Arg Uncertain significance ★ ⚠ same residue
FOXI3 p.Pro85= Likely benign ★ 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

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-pro85ser (accessed [today's date]).

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