Is RBFOX3 p.Arg223Pro (c.668G>C) pathogenic?

RBFOX3 p.Arg223Pro (c.668G>C) is classified Uncertain significance in RBFOX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-25). AlphaMissense: likely pathogenic (0.7658); Very rare (popmax 8.72e-05%, nfe); Associated with idiopathic generalized epilepsy.

What condition is associated with RBFOX3 p.Arg223Pro (c.668G>C)?

RBFOX3 p.Arg223Pro (c.668G>C) is associated with idiopathic generalized epilepsy (ClinVar).

How common is RBFOX3 p.Arg223Pro (c.668G>C) in the general population?

RBFOX3 p.Arg223Pro (c.668G>C) is very rare (popmax 8.72e-05%, nfe) (gnomAD).

What do computational predictors say about RBFOX3 p.Arg223Pro (c.668G>C)?

AlphaMissense predicts likely pathogenic (score 0.7658) — an in-silico prediction, not a clinical call.

RBFOX3 p.Arg223Pro

c.668G>C · rs2510119706 · VCV2901990

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7658 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.72e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

idiopathic generalized epilepsy

Computational evidence

Protein change
AlphaMissense	0.7658	likely pathogenic
REVEL	0.35	indeterminate
SaProt	LLR -9.84	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.4	GERP 0.58, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 7,174 bp · p 0.013 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.72e-05% European (non-Finnish) · 1/1,146,280 alleles

Overall 6.46e-05% 1/1,548,632 alleles · very rare exomes 1/1,396,588 · genomes 0/152,044 · joint denominator

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: RBFOX3
Protein: p.Arg223Pro
Coding: c.668G>C
MANE Select: NM_001350451
dbSNP: rs2510119706
Type: single nucleotide variant
Location: chr17:79097379 (GRCh38)
Gene constraint: LOEUF 0.605 · pLI 0.60 (gnomAD)
Structure: AlphaFold pLDDT 62.27
Residue 223: a modified residue (asymmetric dimethylarginine; alternate); a modified residue (omega-n-methylarginine; alternate)

Full RBFOX3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

idiopathic generalized epilepsy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RBFOX3 p.Ala316Thr Uncertain significance ★★ ⚠ same condition
RBFOX3 p.Ala62Val Uncertain significance ★★ ⚠ same condition
RBFOX3 p.Ala68Thr Uncertain significance ★★ ⚠ same condition
RBFOX3 p.Ala79Val Uncertain significance ★★ ⚠ same condition
RBFOX3 p.Ala8Thr Uncertain significance ★★ ⚠ same condition
RBFOX3 p.Arg230Trp Uncertain significance ★★ ⚠ same condition
RBFOX3 p.Gln31Arg Uncertain significance ★★ ⚠ same condition
RBFOX3 p.Glu61Lys 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/rbfox3-p-arg223pro (accessed [today's date]).

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