Is TONSL p.Leu259fs (c.775_776del) pathogenic?

TONSL p.Leu259fs (c.775776del) is classified Pathogenic in TONSL (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-06). Ultra-rare (gnomAD MAF 1.685e-06).

How common is TONSL p.Leu259fs (c.775_776del) in the general population?

TONSL p.Leu259fs (c.775_776del) is ultra-rare (gnomAD MAF 1.685e-06) (gnomAD).

TONSL p.Leu259fs

c.775_776del · rs1246994520 · VCV1457804

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (gnomAD MAF 1.685e-06)

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 7 of 26
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.13	GERP -2.2, phastCons 0.011

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

Population frequency

dbSNP / gnomAD

Global frequency 0.000169% via dbSNP · ultra-rare

No ancestry breakdown or filtering allele frequency is available for this variant, so BA1/BS1 cannot be assessed from this figure alone.

Variant & gene context

Gene: TONSL
Protein: p.Leu259fs
Coding: c.775_776del
MANE Select: NM_013432
dbSNP: rs1246994520
Type: Deletion
Location: chr8:144442126 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 259: 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

Similar variants

TONSL p.Ser1183fs Pathogenic ★★ same type
TONSL c.3006_3006+1del Likely pathogenic ★ same type
TONSL c.3387+1_3387+19del Likely pathogenic ★ same type
TONSL c.740_750+17del Likely pathogenic ★ same type
TONSL p.Ala371fs Pathogenic ★ same type
TONSL p.Asn182fs Likely pathogenic ★ same type
TONSL p.Asp589fs Pathogenic ★ same type
TONSL p.Asp61fs 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-leu259fs (accessed [today's date]).

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