Is TONSL p.Arg875Ter (c.2623C>T) pathogenic?

TONSL p.Arg875Ter (c.2623C>T) is classified Pathogenic/Likely pathogenic in TONSL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-13). Very rare (popmax 0.00267%, afr); Associated with TONSL-related disorder.

What condition is associated with TONSL p.Arg875Ter (c.2623C>T)?

TONSL p.Arg875Ter (c.2623C>T) is associated with TONSL-related disorder, spondyloepimetaphyseal dysplasia, sponastrime type (ClinVar).

How common is TONSL p.Arg875Ter (c.2623C>T) in the general population?

TONSL p.Arg875Ter (c.2623C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

TONSL p.Arg875Ter

c.2623C>T · rs568942029 · VCV1429349

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

TONSL-related disorder

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 17 of 26
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.21	GERP -3
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 0.00267% African / African-American · 2/75,014 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00062% 10/1,612,796 alleles · very rare exomes 8/1,460,554 · genomes 2/152,242 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,507
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.000593%	168,553

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.Arg875Ter
Coding: c.2623C>T
MANE Select: NM_013432
dbSNP: rs568942029
Type: single nucleotide variant
Location: chr8:144435810 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 875: the 'disordered' region; 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

TONSL-related disorder

Also linked: spondyloepimetaphyseal dysplasia, sponastrime type

Similar variants

TONSL p.Arg875Gln Uncertain significance ★★ ⚠ same residue
TONSL p.Arg875Pro Likely benign ★★ same residue
TONSL c.1891-1G>C Pathogenic/Likely pathogenic ★★ same condition
TONSL p.Arg934Trp Pathogenic ★★ ⚠ same condition
TONSL p.Gln177Ter Pathogenic/Likely pathogenic ★★ same condition
TONSL p.Gln511Ter Pathogenic/Likely pathogenic ★★ same condition
TONSL p.Glu487Lys Pathogenic/Likely pathogenic ★★ ⚠ same condition
TONSL p.Ala1092Val Uncertain significance ★★ ⚠ 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-arg875ter (accessed [today's date]).

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