Is FOXI3 p.Pro85Arg (c.254C>G) pathogenic?

FOXI3 p.Pro85Arg (c.254C>G) is classified Uncertain significance in FOXI3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-29). AlphaMissense: likely benign (0.1599); Very rare (popmax 0.000241%, nfe).

How common is FOXI3 p.Pro85Arg (c.254C>G) in the general population?

FOXI3 p.Pro85Arg (c.254C>G) is very rare (popmax 0.000241%, nfe) (gnomAD).

What do computational predictors say about FOXI3 p.Pro85Arg (c.254C>G)?

AlphaMissense predicts likely benign (score 0.1599) — an in-silico prediction, not a clinical call.

FOXI3 p.Pro85Arg

c.254C>G · rs1008353288 · VCV1510634

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1599 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000241%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.1599	likely benign
SaProt	LLR -13.23	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 7.3	GERP 0.74, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 563 bp · p 0.17 · regional, not allelic
Overall
CADD	21.1	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 0.000241% European (non-Finnish) · 2/829,980 alleles

Filtering AF 4e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.5e-05%

Overall 0.00061% 6/983,232 alleles · very rare exomes 3/837,104 · genomes 3/146,128 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0464%	2,153
European (non-Finnish)grpmax	0.000241%	414,989

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro85Arg
Coding: c.254C>G
MANE Select: NM_001135649
dbSNP: rs1008353288
Type: single nucleotide variant
Location: chr2:88452282 (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.Pro85Ala Uncertain significance ★ ⚠ same residue
FOXI3 p.Pro85Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
FOXI3 p.Pro85= Likely benign ★ same residue
FOXI3 p.Pro85_Gly86dup Uncertain significance ★ same residue
FOXI3 p.Pro85_Gly86insPro Uncertain significance ★ same residue
FOXI3 p.Pro85_Gly86insProPro Uncertain significance ★ same residue
FOXI3 p.Pro85dup Uncertain significance ★ same residue
FOXI3 p.Arg236Trp Likely pathogenic ★★ 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-pro85arg (accessed [today's date]).

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