# NM_013432.5(TONSL):c.3828C>G (p.Pro1276=)

https://sugi.bio/variant/tonsl-p-pro1276

## Summary

**TONSL p.Pro1276= (c.3828C>G)** is classified **Likely benign** in TONSL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-31). Very rare (popmax 0.00237%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs1554878425 · 1 submitter · very rare (popmax 0.00237%, nfe)

## For patients & families {#patients}

This is a change in the TONSL 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 | [TONSL](https://sugi.bio/atlas/gene/TONSL/) |
| Protein change (HGVS p.) | p.Pro1276= |
| Coding change (HGVS c.) | c.3828C>G |
| MANE Select transcript | [NM_013432](https://www.ncbi.nlm.nih.gov/nuccore/NM_013432) |
| dbSNP | [rs1554878425](https://www.ncbi.nlm.nih.gov/snp/rs1554878425/) |
| Variant type | single nucleotide variant |
| Location | chr8:144430519-144430519 (GRCh38) |
| ClinVar | [VCV1568204](https://www.ncbi.nlm.nih.gov/clinvar/variation/1568204/) |

**All HGVS expressions:** `NC_000008.10:g.145655902G>C`, `NC_000008.11:g.144430519G>C`, `NG_029456.2:g.3026C>G`, `NM_013432.5:c.3828C>G`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.31) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 1.11, GERP -1.97, phastCons 1 — weakly conserved position
- CADD: **PHRED 2.311**. 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 deltas (raw): acceptor loss **0.31**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.00**. Largest is acceptor loss, 42 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.00237%** (nfe) · FAF95 0.00165% · FAF99 0.00142% · 28/1,179,264 in the highest group · 29/1,612,350 alleles overall — very rare (popmax 0.00237%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00237% | 42,117 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,434 |

*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}

**TONSL** population constraint: LOEUF 1.024, pLI 2.6737e-33, missense-Z -1.1994. *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 **1276** lies in a UniProt-annotated variant site (in semdsp; disease phenotype includes immunologic and hematologic abnormalities); a UniProt-annotated variant site (in semdsp); a UniProt-annotated variant site (in semdsp; disease phenotype includes primary aphakia and absent pupils); a UniProt-annotated variant site (in).

AlphaFold model confidence (whole protein): pLDDT 76.06, 44% of residues very-high.

**3 experimental structure(s)** (PDB): [5JA4](https://www.rcsb.org/structure/5JA4), [9WVH](https://www.rcsb.org/structure/9WVH), [9WVI](https://www.rcsb.org/structure/9WVI) — incl. mutant structure 9WVI.

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

*Describes the biological roles of TONSL (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:** TONSL's established molecular role includes histone binding.


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

**Molecular function:** histone binding, histone reader activity.

**Biological process:** double-strand break repair via homologous recombination, replication fork processing, protein localization to chromatin.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-12-31.

**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 | 2022-12-31 |

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

## Similar variants {#similar}

Related TONSL variant pages (same residue, condition, or type): [TONSL p.Pro1276Leu](/variant/tonsl-p-pro1276leu), [TONSL c.1891-1G>C](/variant/tonsl-c-1891-minus-1g-c), [TONSL p.Arg875Ter](/variant/tonsl-p-arg875ter), [TONSL p.Arg934Trp](/variant/tonsl-p-arg934trp), [TONSL p.Gln177Ter](/variant/tonsl-p-gln177ter), [TONSL p.Gln511Ter](/variant/tonsl-p-gln511ter), [TONSL p.Glu487Lys](/variant/tonsl-p-glu487lys), [TONSL c.2775+5G>T](/variant/tonsl-c-2775-plus-5g-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1568204). 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.*