Is RBFOX3 p.Pro74= (c.222G>C) pathogenic?

RBFOX3 p.Pro74= (c.222G>C) is classified Uncertain significance in RBFOX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-02). Very rare (popmax 0.000481%, nfe); Associated with idiopathic generalized epilepsy.

What condition is associated with RBFOX3 p.Pro74= (c.222G>C)?

RBFOX3 p.Pro74= (c.222G>C) is associated with idiopathic generalized epilepsy (ClinVar).

How common is RBFOX3 p.Pro74= (c.222G>C) in the general population?

RBFOX3 p.Pro74= (c.222G>C) is very rare (popmax 0.000481%, nfe) (gnomAD).

RBFOX3 p.Pro74=

c.222G>C · rs1037097785 · VCV1365686

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000481%, nfe)

Conditions

idiopathic generalized epilepsy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.58	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.56	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.3	GERP 0.87, phastCons 1
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000481% European (non-Finnish) · 5/1,038,600 alleles

Filtering AF 0.000141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000103%

Overall 0.000452% 6/1,326,314 alleles · very rare exomes 5/1,174,246 · genomes 1/152,068 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00508%	19,694
European (non-Finnish)grpmax	0.000481%	207,720

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: RBFOX3
Protein: p.Pro74=
Coding: c.222G>C
MANE Select: NM_001350451
dbSNP: rs1037097785
Type: single nucleotide variant
Location: chr17:79115494 (GRCh38)
Gene constraint: LOEUF 0.605 · pLI 0.60 (gnomAD)
Structure: AlphaFold pLDDT 62.27
Residue 74: 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.Pro74Gln Uncertain significance ★ ⚠ same residue
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

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-pro74 (accessed [today's date]).

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