# NM_013432.5(TONSL):c.1602_1612del (p.Ala536fs)

https://sugi.bio/variant/tonsl-p-ala536fs

## Summary

**TONSL p.Ala536fs (c.1602_1612del)** is classified **Pathogenic/Likely pathogenic** in TONSL (ClinVar, No assertion criteria, 2 submitters; last evaluated 2019-07-24). No gnomAD frequency available for this variant; Associated with spondyloepimetaphyseal dysplasia, sponastrime type.

**At a glance:** Pathogenic/Likely pathogenic · review: No assertion criteria · rsID rs1586692058 · 2 submitters · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the TONSL gene that is considered likely disease-causing, submitted by 2 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.Ala536fs |
| Coding change (HGVS c.) | c.1602_1612del |
| MANE Select transcript | [NM_013432](https://www.ncbi.nlm.nih.gov/nuccore/NM_013432) |
| dbSNP | [rs1586692058](https://www.ncbi.nlm.nih.gov/snp/rs1586692058/) |
| Variant type | Deletion |
| Location | chr8:144438512-144438522 (GRCh38) |
| ClinVar | [VCV638063](https://www.ncbi.nlm.nih.gov/clinvar/variation/638063/) |

**All HGVS expressions:** `NC_000008.10:g.145663900_145663910del`, `NC_000008.11:g.144438517_144438527del`, `NM_013432.5:c.1602_1612del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 11.045, GERP 1.59, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.024, pLI 2.6737e-33. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 13 of 26**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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 **536** lies in a UniProt-annotated variant site (in semdsp; disease phenotype includes immunologic and hematologic abnormalities); a UniProt-annotated variant site (in semdsp); an α-helix.

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}

**Pathogenic/Likely pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2019-07-24.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Likely pathogenic).

**Submission history:** 2 submissions (2019); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2019-07-24 |
| University of Washington Center for Mendelian Genomics, University of Washington | Likely pathogenic | no assertion criteria provided | research |  |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Sponastrime dysplasia, SPONDYLAR AND NASAL ALTERATIONS WITH STRIATED METAPHYSES.

## Similar variants {#similar}

Related TONSL variant pages (same residue, condition, or type): [TONSL p.Ser1183fs](/variant/tonsl-p-ser1183fs), [TONSL c.3006_3006+1del](/variant/tonsl-c-3006-3006-plus-1del), [TONSL p.Asn182fs](/variant/tonsl-p-asn182fs), [TONSL p.Glu479fs](/variant/tonsl-p-glu479fs), [TONSL p.Pro826fs](/variant/tonsl-p-pro826fs), [TONSL p.Ala536=](/variant/tonsl-p-ala536), [TONSL c.3559+287_3735+546del](/variant/tonsl-c-3559-plus-287-3735-plus-546del), [TONSL c.1891-1G>C](/variant/tonsl-c-1891-minus-1g-c).

### 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 638063). 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.*