# NM_025077.4(TOE1):c.255C>T (p.Tyr85=)

https://sugi.bio/variant/toe1-p-tyr85

## Summary

**TOE1 p.Tyr85= (c.255C>T)** is classified **Likely benign** in TOE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-13). Very rare (popmax 0.00941%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs759850150 · 1 submitter · very rare (popmax 0.00941%, nfe)

## For patients & families {#patients}

This is a change in the TOE1 gene that is classified as likely benign — not considered disease-causing, 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.Tyr85= |
| Coding change (HGVS c.) | c.255C>T |
| MANE Select transcript | [NM_025077](https://www.ncbi.nlm.nih.gov/nuccore/NM_025077) |
| dbSNP | [rs759850150](https://www.ncbi.nlm.nih.gov/snp/rs759850150/) |
| Variant type | single nucleotide variant |
| Location | chr1:45341491-45341491 (GRCh38) |
| ClinVar | [VCV1649756](https://www.ncbi.nlm.nih.gov/clinvar/variation/1649756/) |

**All HGVS expressions:** `LRG_220:g.3980G>A`, `NC_000001.10:g.45807163C>T`, `NC_000001.11:g.45341491C>T`, `NG_008189.1:g.3980G>A`, `NM_025077.4:c.255C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 1.373, GERP -0.191, phastCons 1 — weakly conserved position
- CADD: **PHRED 13.5**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.22 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00941%** (nfe) · FAF95 0.00791% · FAF99 0.00744% · 111/1,180,030 in the highest group · 115/1,614,000 alleles overall — very rare (popmax 0.00941%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00941% | 10,631 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,244 |
| African / African-American | 0.00267% | 37,446 |

*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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-11-13.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-13 |

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

## Similar variants {#similar}

Related TOE1 variant pages (same residue, condition, or type): [MUTYH p.Trp12Ter](/variant/mutyh-p-trp12ter), [TOE1 p.Glu245Ter](/variant/toe1-p-glu245ter), [MUTYH c.36+5G>A](/variant/mutyh-c-36-plus-5g-a), [MUTYH p.Arg10His](/variant/mutyh-p-arg10his), [MUTYH p.Arg7Leu](/variant/mutyh-p-arg7leu), [MUTYH p.Pro3Leu](/variant/mutyh-p-pro3leu), [TOE1 p.Arg184Cys](/variant/toe1-p-arg184cys), [TOE1 p.Arg184His](/variant/toe1-p-arg184his).

### 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 2026-07-14); 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 1649756). 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.*