# NM_025077.4(TOE1):c.668del (p.Pro223fs)

https://sugi.bio/variant/toe1-p-pro223fs

## Summary

**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).

**At a glance:** Pathogenic · review: Single submitter · rsID rs767479473 · 1 submitter · very rare (popmax 0.00833%, amr)

## For patients & families {#patients}

This is a change in the TOE1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TOE1](https://sugi.bio/atlas/gene/TOE1/) |
| Protein change (HGVS p.) | p.Pro223fs |
| Coding change (HGVS c.) | c.668del |
| MANE Select transcript | [NM_025077](https://www.ncbi.nlm.nih.gov/nuccore/NM_025077) |
| dbSNP | [rs767479473](https://www.ncbi.nlm.nih.gov/snp/rs767479473/) |
| Variant type | Deletion |
| Location | chr1:45342557-45342557 (GRCh38) |
| ClinVar | [VCV1986984](https://www.ncbi.nlm.nih.gov/clinvar/variation/1986984/) |

**All HGVS expressions:** `LRG_220:g.2914del`, `NC_000001.10:g.45808231del`, `NC_000001.11:g.45342559del`, `NG_008189.1:g.2914del`, `NM_025077.4:c.668del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 6.165, GERP 0.766, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.225, pLI 5.2565e-17. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 6 of 8**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00833%** (amr) · FAF95 0.00323% · FAF99 0.00206% · 5/60,018 in the highest group · 5/1,614,164 alleles overall — very rare (popmax 0.00833%, amr).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**TOE1** population constraint: LOEUF 1.225, pLI 5.2565e-17, missense-Z 2.0223. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 79.16, 63% of residues very-high.

**1 experimental structure(s)** (PDB): [2FC6](https://www.rcsb.org/structure/2FC6).

## What this gene does {#gene-function}

*Describes the biological roles of TOE1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** TOE1's established molecular role includes 3'-5'-RNA exonuclease activity.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** 3'-5'-RNA exonuclease activity, poly(A)-specific ribonuclease activity, snRNA binding.

**Biological process:** snRNA 3'-end processing.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-02-02.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-02-02 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related TOE1 variant pages (same residue, condition, or type): [TOE1 p.Asn255fs](/variant/toe1-p-asn255fs), [TOE1 p.Asn391fs](/variant/toe1-p-asn391fs), [TOE1 p.Gln108fs](/variant/toe1-p-gln108fs), [TOE1 p.Thr355fs](/variant/toe1-p-thr355fs), [TOE1 c.334-5_334-3del](/variant/toe1-c-334-minus-5-334-minus-3del), [TOE1 p.Glu413_Ile414insTer](/variant/toe1-p-glu413-ile414inster), [TOE1 p.Lys502fs](/variant/toe1-p-lys502fs), [TOE1 c.753-9_753-7del](/variant/toe1-c-753-minus-9-753-minus-7del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1986984). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*