Is TONSL p.Asp1267fs (c.3799_3800insT) pathogenic?

TONSL p.Asp1267fs (c.37993800insT) is classified Pathogenic in TONSL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-30). Very rare (popmax 0.000186%).

How common is TONSL p.Asp1267fs (c.3799_3800insT) in the general population?

TONSL p.Asp1267fs (c.3799_3800insT) is very rare (popmax 0.000186%) (gnomAD).

TONSL p.Asp1267fs

c.3799_3800insT · VCV3663392

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000186%)

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 24 of 26
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.7	GERP -0.37, phastCons 0.003

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000186%

Overall 0.000186% 3/1,614,022 alleles · very rare exomes 3/1,461,808 · genomes 0/152,214 · joint denominator

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.Asp1267fs
Coding: c.3799_3800insT
MANE Select: NM_013432
Type: Insertion
Location: chr8:144431087 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 1267: 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

Similar variants

TONSL p.Ala819fs Pathogenic ★ same type

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-asp1267fs (accessed [today's date]).

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