Is TONSL p.Pro1204fs (c.3611del) pathogenic?

TONSL p.Pro1204fs (c.3611del) is classified Conflicting classifications of pathogenicity in TONSL (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-18). Ultra-rare (popmax 0.0129%, amr).

How common is TONSL p.Pro1204fs (c.3611del) in the general population?

TONSL p.Pro1204fs (c.3611del) is ultra-rare (popmax 0.0129%, amr) (gnomAD).

TONSL p.Pro1204fs

c.3611del · rs782628825 · VCV2574446

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0129%, 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 23 of 26
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -6.7	GERP -3.3
Overall
CADD	22.0	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 0.0129% Admixed American · 7/54,458 alleles

Filtering AF 0.00602% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00422%

Overall 0.00044% 7/1,589,860 alleles · ultra-rare exomes 4/1,437,698 · genomes 3/152,162 · joint denominator

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.Pro1204fs
Coding: c.3611del
MANE Select: NM_013432
dbSNP: rs782628825
Type: Deletion
Location: chr8:144432409 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 1204: 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.Pro1204His Uncertain significance ★ ⚠ same residue
TONSL p.Pro1204Ser Uncertain significance ★ ⚠ same residue
TONSL p.Pro1204Tyr Uncertain significance ★ same residue
TONSL p.Pro1204= Likely benign ★ 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

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-pro1204fs (accessed [today's date]).

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