Is TONSL p.469EEA[3] (c.1406AGGAGGCGG[3]) pathogenic?

TONSL p.469EEA[3] (c.1406AGGAGGCGG[3]) is classified Uncertain significance in TONSL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-07-29). Ultra-rare (popmax 0.0424%, eas).

How common is TONSL p.469EEA[3] (c.1406AGGAGGCGG[3]) in the general population?

TONSL p.469EEA[3] (c.1406AGGAGGCGG[3]) is ultra-rare (popmax 0.0424%, eas) (gnomAD).

TONSL p.469EEA[3]

c.1406AGGAGGCGG[3] · rs534884350 · VCV1412364

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0424%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.87	GERP -3
Overall
CADD	2.004	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	(CTCCGC)n simple repeat · ambiguous alignment · confidence, not pathogenicity

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0424% East Asian · 19/44,780 alleles

Filtering AF 0.0277% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.023%

Overall 0.00383% 61/1,594,662 alleles · ultra-rare exomes 54/1,442,524 · genomes 7/152,138 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0424%	2,357
Middle Eastern	0.0166%	6,040
Remaining individualsnot grpmax-eligible	0.00485%	20,601
South Asian	0.00441%	22,662
Ashkenazi Jewishnot grpmax-eligible	0.0034%	29,454
European (non-Finnish)	0.00275%	36,384
Admixed American	0.00168%	59,552

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.469EEA[3]
Coding: c.1406AGGAGGCGG[3]
MANE Select: NM_013432
dbSNP: rs534884350
Type: Microsatellite
Location: chr8:144440077 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB

Full TONSL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TONSL p.Glu983fs Pathogenic ★ 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-469eea-3 (accessed [today's date]).

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