Is TOE1 p.Pro223fs (c.668del) pathogenic?

TOE1 p.Pro223fs (c.668del) is classified Pathogenic in TOE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-02). Very rare (popmax 0.00833%, amr).

How common is TOE1 p.Pro223fs (c.668del) in the general population?

TOE1 p.Pro223fs (c.668del) is very rare (popmax 0.00833%, amr) (gnomAD).

TOE1 p.Pro223fs

c.668del · rs767479473 · VCV1986984

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 8
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.2	GERP 0.77, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00833% Admixed American · 5/60,018 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00206%

Overall 0.000342% 5/1,461,890 alleles · very rare

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: TOE1
Protein: p.Pro223fs
Coding: c.668del
MANE Select: NM_025077
dbSNP: rs767479473
Type: Deletion
Location: chr1:45342557 (GRCh38)
Gene constraint: LOEUF 1.225 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.16 · 1 PDB

Full TOE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TOE1 p.Asn255fs Likely pathogenic ★ same type
TOE1 p.Asn391fs Likely pathogenic ★ same type
TOE1 p.Gln108fs Likely pathogenic ★ same type
TOE1 p.Thr355fs Likely pathogenic ★ same type
TOE1 c.334-5_334-3del Uncertain significance ★ same type
TOE1 p.Glu413_Ile414insTer Uncertain significance ★ same type
TOE1 p.Lys502fs Uncertain significance ★ same type
TOE1 c.753-9_753-7del Likely benign ★ 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/toe1-p-pro223fs (accessed [today's date]).

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