# NM_013432.5(TONSL):c.1837G>T (p.Val613Leu)

https://sugi.bio/variant/tonsl-p-val613leu

## Summary

**TONSL p.Val613Leu (c.1837G>T)** is classified **Uncertain significance** in TONSL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-16). AlphaMissense: likely pathogenic (0.8932); Absent from gnomAD v4.1; Associated with spondyloepimetaphyseal dysplasia, sponastrime type.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs778625348 · 3 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the TONSL gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 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.Val613Leu |
| Coding change (HGVS c.) | c.1837G>T |
| MANE Select transcript | [NM_013432](https://www.ncbi.nlm.nih.gov/nuccore/NM_013432) |
| dbSNP | [rs778625348](https://www.ncbi.nlm.nih.gov/snp/rs778625348/) |
| Variant type | single nucleotide variant |
| Location | chr8:144436810-144436810 (GRCh38) |
| ClinVar | [VCV638579](https://www.ncbi.nlm.nih.gov/clinvar/variation/638579/) |

**All HGVS expressions:** `NC_000008.10:g.145662193C>A`, `NC_000008.11:g.144436810C>A`, `NM_013432.5:c.1837G>T`, `NR_109770.1:n.333C>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8932)
- REVEL 0.54 (indeterminate)
- SaProt LLR -10.471 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- Conservation: phyloP 7.603, GERP 1.49, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 7%** most-pathogenic-predicted substitutions in TONSL (of 8,074 modeled).
- CADD: **PHRED 25.9**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **613** 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; uncertain significance); 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-05-16.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 Likely pathogenic).

**Submission history:** 3 submissions (2016–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| University of Washington Center for Mendelian Genomics, University of Washington | Likely pathogenic | no assertion criteria provided | research |  |
| Undiagnosed Diseases Network, NIH | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-11-04 |
| 3billion | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-05-16 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Sponastrime dysplasia, TONSL-related disorder, Skeletal dysplaisia with extra-skeletal manifestations, SPONDYLAR AND NASAL ALTERATIONS WITH STRIATED METAPHYSES, TONSL-related condition.

## 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 2026-10-14); 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 638579). 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.*