Is RBFOX3 p.Pro40Ser (c.118C>T) pathogenic?

RBFOX3 p.Pro40Ser (c.118C>T) is classified Uncertain significance in RBFOX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-13). AlphaMissense: likely benign (0.0675); Very rare (popmax 0.00147%, afr); Associated with idiopathic generalized epilepsy.

What condition is associated with RBFOX3 p.Pro40Ser (c.118C>T)?

RBFOX3 p.Pro40Ser (c.118C>T) is associated with idiopathic generalized epilepsy (ClinVar).

How common is RBFOX3 p.Pro40Ser (c.118C>T) in the general population?

RBFOX3 p.Pro40Ser (c.118C>T) is very rare (popmax 0.00147%, afr) (gnomAD).

What do computational predictors say about RBFOX3 p.Pro40Ser (c.118C>T)?

AlphaMissense predicts likely benign (score 0.0675) — an in-silico prediction, not a clinical call.

RBFOX3 p.Pro40Ser

c.118C>T · rs1298625389 · VCV961789

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0675 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00147%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

idiopathic generalized epilepsy

Computational evidence

Protein change
AlphaMissense	0.0675	likely benign
REVEL	0.096	moderately benign-leaning
SaProt	LLR -6.29	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8	GERP 1.2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 8,995 bp · p 0.22 · regional, not allelic
Overall
CADD	22.7	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; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00147% African / African-American · 1/68,144 alleles

Overall 6.99e-05% 1/1,430,592 alleles · very rare exomes 0/1,278,882 · genomes 1/151,710 · 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.Pro40Ser
Coding: c.118C>T
MANE Select: NM_001350451
dbSNP: rs1298625389
Type: single nucleotide variant
Location: chr17:79115598 (GRCh38)
Gene constraint: LOEUF 0.605 · pLI 0.60 (gnomAD)
Structure: AlphaFold pLDDT 62.27
Residue 40: the 'disordered' region

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-pro40ser (accessed [today's date]).

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