# NM_013432.5(TONSL):c.1462G>A (p.Val488Met)

https://sugi.bio/variant/tonsl-p-val488met

## Summary

**TONSL p.Val488Met (c.1462G>A)** is classified **Benign** in TONSL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1183); Common (popmax 6.64%, afr) — too common for a highly-penetrant pathogenic allele.

**At a glance:** Benign · review: Multiple submitters · rsID rs2229314 · 3 submitters · AlphaMissense likely benign · common (popmax 6.64%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the TONSL gene that is classified as benign — not considered disease-causing, submitted by 3 submitters.

*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.Val488Met |
| Coding change (HGVS c.) | c.1462G>A |
| MANE Select transcript | [NM_013432](https://www.ncbi.nlm.nih.gov/nuccore/NM_013432) |
| dbSNP | [rs2229314](https://www.ncbi.nlm.nih.gov/snp/rs2229314/) |
| Variant type | single nucleotide variant |
| Location | chr8:144440039-144440039 (GRCh38) |
| ClinVar | [VCV716094](https://www.ncbi.nlm.nih.gov/clinvar/variation/716094/) |

**All HGVS expressions:** `NC_000008.10:g.145665422C>T`, `NC_000008.11:g.144440039C>T`, `NM_013432.5:c.1462G>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 6.64%, afr) — too common for a highly-penetrant pathogenic allele.

- AlphaMissense **likely benign** (0.1183)
- REVEL 0.065 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.869 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor loss** (Δ 0.75) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -2.085, GERP -3.94 — fast-evolving / accelerated position
- CADD: **PHRED 2.622**. 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 1.01** across the covering region of the MANE Select transcript (144,429,146–144,444,414), spanning 15,268 bp. Chi-square p 0.67. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.75**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 1 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 **6.64%** (afr) · FAF95 6.49% · FAF99 6.42% · 4,713/70,938 in the highest group · 5,263/1,404,268 alleles overall — common (popmax 6.64%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 6.64% | 15 |
| Admixed American | 0.445% | 225 |
| Remaining individuals (not grpmax-eligible) | 0.412% | 243 |
| Middle Eastern | 0.106% | 940 |
| South Asian | 0.0173% | 5,784 |
| European (non-Finnish) | 0.00374% | 26,770 |

*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 **488** lies in the 'disordered' region; 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).

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. p.Val488Met falls in the disordered region.


### 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}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-02.

**Submitter consensus:** unanimous (3/3 Benign).

**Submission history:** 3 submissions (2020–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2020-02-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-02 |

**Reported phenotype names (ClinVar):** not provided, TONSL-related disorder, none provided, TONSL-related condition.

## Similar variants {#similar}

Related TONSL variant pages (same residue, condition, or type): [TONSL p.Val488=](/variant/tonsl-p-val488), [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 2026-10-14); 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 716094). 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.*