Is TONSL p.Val957fs (c.2870_2871del) pathogenic?

TONSL p.Val957fs (c.28702871del) is classified Pathogenic in TONSL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-10). Very rare (popmax 0.00136%, afr).

How common is TONSL p.Val957fs (c.2870_2871del) in the general population?

TONSL p.Val957fs (c.2870_2871del) is very rare (popmax 0.00136%, afr) (gnomAD).

TONSL p.Val957fs

c.2870_2871del · VCV4701007

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00136%, afr)

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 3.4	GERP 0.5, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00136% African / African-American · 1/73,682 alleles

Overall 0.000128% 2/1,563,690 alleles · very rare exomes 2/1,411,316 · genomes 0/152,374 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00136%	73,682
European (non-Finnish)	8.66e-05%	1,155,223

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.Val957fs
Coding: c.2870_2871del
MANE Select: NM_013432
Type: Microsatellite
Location: chr8:144435152 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 957: 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.Val957Ala Uncertain significance ★ ⚠ same residue
TONSL p.469EEA[3] Uncertain significance ★★ same type
TONSL p.Glu983fs Pathogenic ★ same type
TONSL p.Leu1274fs 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

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-val957fs (accessed [today's date]).

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