Is TONSL p.Pro826fs (c.2477del) pathogenic?

TONSL p.Pro826fs (c.2477del) is classified Likely pathogenic in TONSL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). Associated with spondyloepimetaphyseal dysplasia, sponastrime type.

What condition is associated with TONSL p.Pro826fs (c.2477del)?

TONSL p.Pro826fs (c.2477del) is associated with spondyloepimetaphyseal dysplasia, sponastrime type (ClinVar).

How is SPONASTRIME dysplasia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

TONSL p.Pro826fs

c.2477del · VCV4846953

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

spondyloepimetaphyseal dysplasia, sponastrime type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 17 of 26
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -8.2	GERP -3

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: TONSL
Protein: p.Pro826fs
Coding: c.2477del
MANE Select: NM_013432
Type: Deletion
Location: chr8:144435956 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 826: 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)

Full TONSL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spondyloepimetaphyseal dysplasia, sponastrime type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For SPONASTRIME dysplasia (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

TONSL p.Ser1183fs Pathogenic ★★ same condition
TONSL c.3006_3006+1del Likely pathogenic ★ same condition
TONSL p.Asn182fs Likely pathogenic ★ same condition
TONSL p.Glu479fs Likely pathogenic ★ same condition
TONSL p.Pro826= Likely benign ★ same residue
TONSL c.3559+287_3735+546del Pathogenic same condition
TONSL p.Ala536fs Pathogenic/Likely pathogenic same condition
TONSL c.1891-1G>C Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tonsl-p-pro826fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown