Is TONSL p.Ser491fs (c.1471_1472del) pathogenic?

TONSL p.Ser491fs (c.14711472del) is classified Uncertain significance in TONSL (ClinVar, Single submitter, 1 submitter). No allele count reported in gnomAD v4.1 (AN 1,300,298); Associated with spondyloepimetaphyseal dysplasia, sponastrime type.

What condition is associated with TONSL p.Ser491fs (c.1471_1472del)?

TONSL p.Ser491fs (c.1471_1472del) is associated with spondyloepimetaphyseal dysplasia, sponastrime type (ClinVar).

How common is TONSL p.Ser491fs (c.1471_1472del) in the general population?

TONSL p.Ser491fs (c.1471_1472del) is no allele count reported in gnomAD v4.1 (AN 1,300,298) (gnomAD).

How is SPONASTRIME dysplasia inherited?

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

TONSL p.Ser491fs

c.1471_1472del · rs2129675776 · VCV1332828

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,300,298)

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 11 of 26
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -12	GERP -3.6

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

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,300,298). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: TONSL
Protein: p.Ser491fs
Coding: c.1471_1472del
MANE Select: NM_013432
dbSNP: rs2129675776
Type: Microsatellite
Location: chr8:144440029 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 491: the 'disordered' region; a UniProt-annotated variant site (in semdsp; disease phenotype includes immunologic and hematologic abnormalities); a UniProt-annotated variant site (in semdsp)

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.Leu664del Uncertain significance ★ same condition
TONSL c.1891-1G>C Pathogenic/Likely pathogenic ★★ same condition
TONSL p.Arg875Ter Pathogenic/Likely pathogenic ★★ same condition
TONSL p.Arg934Trp Pathogenic ★★ ⚠ same condition
TONSL p.Gln511Ter Pathogenic/Likely pathogenic ★★ same condition
TONSL p.Glu487Lys Pathogenic/Likely pathogenic ★★ ⚠ same condition
TONSL p.Leu225fs Pathogenic/Likely pathogenic ★★ same condition
TONSL p.Ser1183fs 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-ser491fs (accessed [today's date]).

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