Is TONSL p.Ser1183fs (c.3549del) pathogenic?

TONSL p.Ser1183fs (c.3549del) is classified Pathogenic in TONSL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-08). Very rare (popmax 0.0072%, nfe); Associated with spondyloepimetaphyseal dysplasia, sponastrime type.

What condition is associated with TONSL p.Ser1183fs (c.3549del)?

TONSL p.Ser1183fs (c.3549del) is associated with spondyloepimetaphyseal dysplasia, sponastrime type (ClinVar).

How common is TONSL p.Ser1183fs (c.3549del) in the general population?

TONSL p.Ser1183fs (c.3549del) is very rare (popmax 0.0072%, nfe) (gnomAD).

How is SPONASTRIME dysplasia inherited?

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

TONSL p.Ser1183fs

c.3549del · rs782201765 · VCV1805067

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0072%, nfe)

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 22 of 26
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.2	GERP 1.8, phastCons 1
Overall
CADD	14.57	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0072% European (non-Finnish) · 85/1,179,926 alleles

Filtering AF 0.00596% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00549%

Overall 0.00552% 89/1,613,268 alleles · very rare exomes 88/1,461,008 · genomes 1/152,260 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0072%	13,881
Remaining individualsnot grpmax-eligible	0.0048%	20,821
South Asian	0.0011%	91,072

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TONSL
Protein: p.Ser1183fs
Coding: c.3549del
MANE Select: NM_013432
dbSNP: rs782201765
Type: Deletion
Location: chr8:144433598 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 1183: 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 c.3006_3006+1del Likely pathogenic ★ same condition
TONSL p.Asn182fs Likely pathogenic ★ same condition
TONSL p.Glu479fs Likely pathogenic ★ same condition
TONSL p.Pro826fs Likely pathogenic ★ same condition
TONSL p.Ser1183Asn Uncertain significance ★ ⚠ same residue
TONSL p.Ser1183= Likely benign ★ same residue
TONSL c.3559+287_3735+546del Pathogenic same condition
TONSL p.Ala536fs 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-ser1183fs (accessed [today's date]).

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