# NM_013432.5(TONSL):c.2496C>T (p.Ala832=)

https://sugi.bio/variant/tonsl-p-ala832

## Summary

**TONSL p.Ala832= (c.2496C>T)** is classified **Benign** in TONSL (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 57.8%, sas) — too common for a highly-penetrant pathogenic allele; Associated with spondyloepimetaphyseal dysplasia, sponastrime type.

**At a glance:** Benign · review: Multiple submitters · rsID rs2721140 · 4 submitters · 1 linked condition · common (popmax 57.8%, sas) — 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 4 submitters, and is linked to spondyloepimetaphyseal dysplasia, sponastrime type.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | TONSL is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of SPONASTRIME dysplasia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of the vertebral column — Very frequent (99-80%)
- Platyspondyly — Very frequent (99-80%)
- Abnormal facial shape — Very frequent (99-80%)
- Depressed nasal bridge — Very frequent (99-80%)
- Disproportionate short-limb short stature — Very frequent (99-80%)
- Midface retrusion — Very frequent (99-80%)
- Brachydactyly — Frequent (79-30%)
- Intrauterine growth retardation — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0004970/index) · [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.Ala832= |
| Coding change (HGVS c.) | c.2496C>T |
| MANE Select transcript | [NM_013432](https://www.ncbi.nlm.nih.gov/nuccore/NM_013432) |
| dbSNP | [rs2721140](https://www.ncbi.nlm.nih.gov/snp/rs2721140/) |
| Variant type | single nucleotide variant |
| Location | chr8:144435937-144435937 (GRCh38) |
| ClinVar | [VCV1167020](https://www.ncbi.nlm.nih.gov/clinvar/variation/1167020/) |

**All HGVS expressions:** `NC_000008.10:g.145661320G>A`, `NC_000008.11:g.144435937G>A`, `NM_013432.5:c.2496C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 57.8%, sas) — too common for a highly-penetrant pathogenic allele.

- **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 -2.981, GERP -3.01 — fast-evolving / accelerated position
- CADD: **PHRED 0.224**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for TONSL (1,220 scored positions, the nearest 10 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **57.8%** (sas) · FAF95 57.4% · FAF99 57.2% · 49,872/86,214 in the highest group · 732,512/1,565,840 alleles overall — common (popmax 57.8%, sas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 57.8% | 2 |
| Amish (not grpmax-eligible) | 51.5% | 2 |
| Finnish (not grpmax-eligible) | 48% | 2 |
| European (non-Finnish) | 47.3% | 2 |
| Remaining individuals (not grpmax-eligible) | 45.5% | 2 |
| Admixed American | 42.3% | 2 |
| African / African-American | 41.7% | 2 |
| East Asian | 37.1% | 3 |
| Middle Eastern | 36.5% | 3 |
| Ashkenazi Jewish (not grpmax-eligible) | 32% | 3 |

*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 **832** 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).

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}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** unanimous (4/4 Benign).

**Submission history:** 4 submissions (2021–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-09-10 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-27 |

## Associated conditions {#conditions}

[spondyloepimetaphyseal dysplasia, sponastrime type](https://sugi.bio/atlas/disease/spondyloepimetaphyseal-dysplasia-sponastrime-type/).

**Reported phenotype names (ClinVar):** Sponastrime dysplasia, not provided, not specified, AllHighlyPenetrant, none provided, SPONDYLAR AND NASAL ALTERATIONS WITH STRIATED METAPHYSES.

## Similar variants {#similar}

Related TONSL variant pages (same residue, condition, or type): [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.Gln511Ter](/variant/tonsl-p-gln511ter), [TONSL p.Glu487Lys](/variant/tonsl-p-glu487lys), [TONSL p.Ala1092Val](/variant/tonsl-p-ala1092val), [TONSL p.Ala192Val](/variant/tonsl-p-ala192val), [TONSL p.Ala964Val](/variant/tonsl-p-ala964val).

### 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 1167020). 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.*