Is TONSL p.Leu164fs (c.490del) pathogenic?

TONSL p.Leu164fs (c.490del) is classified Pathogenic in TONSL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-26). Very rare (popmax 0.00167%, amr).

How common is TONSL p.Leu164fs (c.490del) in the general population?

TONSL p.Leu164fs (c.490del) is very rare (popmax 0.00167%, amr) (gnomAD).

TONSL p.Leu164fs

c.490del · VCV4709662

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

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 5 of 26
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Overall
CADD	31.0	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 0.00167% Admixed American · 1/59,988 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000806% 13/1,612,734 alleles · very rare exomes 11/1,460,582 · genomes 2/152,152 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,988
European (non-Finnish)	0.00102%	98,326

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.Leu164fs
Coding: c.490del
MANE Select: NM_013432
Type: Deletion
Location: chr8:144442765 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 164: 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.Leu164Val Uncertain significance ★ same residue
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

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-leu164fs (accessed [today's date]).

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