Is TONSL p.Arg263Ter (c.787C>T) pathogenic?

TONSL p.Arg263Ter (c.787C>T) is classified Pathogenic in TONSL (ClinVar, Single submitter, 2 submitters; last evaluated 2025-11-18). Very rare (popmax 0.00445%, eas); Associated with spondyloepimetaphyseal dysplasia, sponastrime type.

What condition is associated with TONSL p.Arg263Ter (c.787C>T)?

TONSL p.Arg263Ter (c.787C>T) is associated with spondyloepimetaphyseal dysplasia, sponastrime type (ClinVar).

How common is TONSL p.Arg263Ter (c.787C>T) in the general population?

TONSL p.Arg263Ter (c.787C>T) is very rare (popmax 0.00445%, eas) (gnomAD).

How is SPONASTRIME dysplasia inherited?

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

TONSL p.Arg263Ter

c.787C>T · rs372806119 · VCV1343381

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Conditions

spondyloepimetaphyseal dysplasia, sponastrime type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 26
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -2.6, phastCons 0.99
Overall
CADD	37.0	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 0.00445% East Asian · 2/44,894 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.00093% 15/1,612,508 alleles · very rare exomes 12/1,460,278 · genomes 3/152,230 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,447
African / African-American	0.00267%	37,456
South Asian	0.0011%	91,074
European (non-Finnish)	0.000848%	117,983

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.Arg263Ter
Coding: c.787C>T
MANE Select: NM_013432
dbSNP: rs372806119
Type: single nucleotide variant
Location: chr8:144442115 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 263: 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.Arg263Gln Uncertain significance ★★ ⚠ same residue
TONSL p.Arg263Pro Uncertain significance ★ ⚠ same residue
TONSL p.Arg263= Likely benign ★ same residue
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

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-arg263ter (accessed [today's date]).

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