# NM_003260.5(TLE2):c.1036T>C (p.Ser346Pro)

https://sugi.bio/variant/tle2-p-ser346pro

## Summary

**TLE2 p.Ser346Pro (c.1036T>C)** is classified **Uncertain significance** in TLE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-28). AlphaMissense: likely benign (0.0689); Ultra-rare (popmax 0.0379%, eas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs759549616 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0379%, eas)

## For patients & families {#patients}

This is a change in the TLE2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [TLE2](https://sugi.bio/atlas/gene/TLE2/) |
| Protein change (HGVS p.) | p.Ser346Pro |
| Coding change (HGVS c.) | c.1036T>C |
| MANE Select transcript | [NM_003260](https://www.ncbi.nlm.nih.gov/nuccore/NM_003260) |
| dbSNP | [rs759549616](https://www.ncbi.nlm.nih.gov/snp/rs759549616/) |
| Variant type | single nucleotide variant |
| Location | chr19:3009679-3009679 (GRCh38) |
| ClinVar | [VCV2490733](https://www.ncbi.nlm.nih.gov/clinvar/variation/2490733/) |

**All HGVS expressions:** `NC_000019.10:g.3009679A>G`, `NC_000019.9:g.3009677A>G`, `NM_001144761.2:c.1078T>C`, `NM_001144762.2:c.670T>C`, `NM_001300846.2:c.1039T>C`, `NM_003260.5:c.1036T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0689)
- REVEL 0.058 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.885 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor loss** (Δ 0.26) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 1.73, phastCons 0.999 — weakly conserved position
- CADD: **PHRED 18.78**. 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.*
- Regional missense constraint: **o/e 1.03** across the covering region of the MANE Select transcript (2,997,851–3,028,904), spanning 31,053 bp. Chi-square p 0.36. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.26**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.26**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0379%** (eas) · FAF95 0.0241% · FAF99 0.0198% · 17/44,862 in the highest group · 24/1,612,558 alleles overall — ultra-rare (popmax 0.0379%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0379% | 2,639 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,428 |
| European (non-Finnish) | 0.000509% | 196,565 |

*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}

**TLE2** population constraint: LOEUF 1.02, pLI 1.8431e-21, missense-Z -0.83722. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **346** lies in the 'sp domain' region.

AlphaFold model confidence (whole protein): pLDDT 68.40, 41% of residues very-high.

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

*Describes the biological roles of TLE2 (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:** TLE2's established molecular role includes transcription corepressor activity. p.Ser346Pro falls in the sp domain region.


### Pathways affected {#pathways}

TLE2 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Deactivation of the beta-catenin transactivating complex](https://reactome.org/content/detail/R-HSA-3769402) | curated |
| [Formation of the beta-catenin:TCF transactivating complex](https://reactome.org/content/detail/R-HSA-201722) | curated |
| [NOTCH1 Intracellular Domain Regulates Transcription](https://reactome.org/content/detail/R-HSA-2122947) | electronic |
| [Repression of WNT target genes](https://reactome.org/content/detail/R-HSA-4641265) | electronic |

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

**Molecular function:** transcription corepressor activity.

**Biological process:** negative regulation of DNA-templated transcription, negative regulation of canonical Wnt signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-02-28.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-02-28 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related TLE2 variant pages (same residue, condition, or type): [TLE2 p.Ala110Thr](/variant/tle2-p-ala110thr), [TLE2 p.Ala133Val](/variant/tle2-p-ala133val), [TLE2 p.Ala164Val](/variant/tle2-p-ala164val), [TLE2 p.Ala167Val](/variant/tle2-p-ala167val), [TLE2 p.Ala168Val](/variant/tle2-p-ala168val), [TLE2 p.Ala187Ser](/variant/tle2-p-ala187ser), [TLE2 p.Ala187Val](/variant/tle2-p-ala187val), [TLE2 p.Ala192Val](/variant/tle2-p-ala192val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2490733). 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.*