Is TONSL p.Ala221fs (c.659dup) pathogenic?

TONSL p.Ala221fs (c.659dup) is classified Likely pathogenic in TONSL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-19). No gnomAD frequency available for this variant; Associated with TONSL-related disorder.

What condition is associated with TONSL p.Ala221fs (c.659dup)?

TONSL p.Ala221fs (c.659dup) is associated with TONSL-related disorder (ClinVar).

How common is TONSL p.Ala221fs (c.659dup) in the general population?

TONSL p.Ala221fs (c.659dup) is no gnomAD frequency available for this variant (gnomAD).

TONSL p.Ala221fs

c.659dup · rs2537506917 · VCV2632517

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

TONSL-related disorder

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 6 of 26
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.85	GERP 0.38, phastCons 1

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. 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.Ala221fs
Coding: c.659dup
MANE Select: NM_013432
dbSNP: rs2537506917
Type: Duplication
Location: chr8:144442331 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 221: 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

TONSL-related disorder

Similar variants

TONSL p.Ala221= Likely benign ★ same residue
TONSL p.Arg875Ter Pathogenic/Likely pathogenic ★★ same condition
TONSL p.Gln177Ter Pathogenic/Likely pathogenic ★★ same condition
TONSL p.Arg382His Uncertain significance ★★ ⚠ same condition
TONSL p.Glu199Lys Uncertain significance ★★ same condition
TONSL c.3007-2A>C Likely pathogenic ★ same condition
TONSL p.Cys762fs Likely pathogenic ★ same condition
TONSL p.Gln88Ter 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-ala221fs (accessed [today's date]).

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