Is TONSL p.Glu983fs (c.2948_2949del) pathogenic?

TONSL p.Glu983fs (c.29482949del) is classified Pathogenic in TONSL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-03). Ultra-rare (popmax 0.0166%, mid).

How common is TONSL p.Glu983fs (c.2948_2949del) in the general population?

TONSL p.Glu983fs (c.2948_2949del) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

TONSL p.Glu983fs

c.2948_2949del · rs1396762844 · VCV2837378

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

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 19 of 26
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Overall
CADD	34.0	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 0.0166% Middle Eastern · 1/6,014 alleles

Overall 0.00031% 5/1,610,496 alleles · ultra-rare exomes 4/1,458,264 · genomes 1/152,232 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,014
Remaining individualsnot grpmax-eligible	0.00321%	31,155
Admixed American	0.00167%	59,758
European (non-Finnish)	8.48e-05%	1,178,910

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.Glu983fs
Coding: c.2948_2949del
MANE Select: NM_013432
dbSNP: rs1396762844
Type: Microsatellite
Location: chr8:144435074 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 983: 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.469EEA[3] Uncertain significance ★★ same type
TONSL p.Leu1274fs Pathogenic ★ same type
TONSL p.Val957fs Pathogenic ★ same type
TONSL p.464DE[1] Uncertain significance ★ same type
TONSL p.469EEA[1] Uncertain significance ★ same type
TONSL p.Asp496del Uncertain significance ★ same type
TONSL p.Glu468_Glu470dup Uncertain significance ★ same type
TONSL p.Glu470del Uncertain significance ★ 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-glu983fs (accessed [today's date]).

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