Is TONSL p.Arg294Trp (c.880C>T) pathogenic?

TONSL p.Arg294Trp (c.880C>T) is classified Uncertain significance in TONSL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-07). AlphaMissense: likely benign (0.1235); Very rare (popmax 0.00446%, eas).

How common is TONSL p.Arg294Trp (c.880C>T) in the general population?

TONSL p.Arg294Trp (c.880C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about TONSL p.Arg294Trp (c.880C>T)?

AlphaMissense predicts likely benign (score 0.1235) — an in-silico prediction, not a clinical call.

TONSL p.Arg294Trp

c.880C>T · rs946882247 · VCV1385312

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1235 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1235	likely benign
REVEL	0.256	benign-leaning
SaProt	LLR -11.03	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP -0.51, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,878 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00112% 18/1,612,780 alleles · very rare exomes 16/1,460,470 · genomes 2/152,310 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,439
South Asian	0.0022%	45,542
Remaining individualsnot grpmax-eligible	0.0016%	62,478
European (non-Finnish)	0.0011%	90,766

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.Arg294Trp
Coding: c.880C>T
MANE Select: NM_013432
dbSNP: rs946882247
Type: single nucleotide variant
Location: chr8:144441097 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 294: 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.Arg294= Likely benign ★★ same residue
TONSL p.Arg294Leu Uncertain significance ★ ⚠ same residue
TONSL c.1891-1G>C Pathogenic/Likely pathogenic ★★ same type
TONSL p.Arg875Ter Pathogenic/Likely pathogenic ★★ same type
TONSL p.Arg934Trp Pathogenic ★★ ⚠ same type
TONSL p.Gln177Ter Pathogenic/Likely pathogenic ★★ same type
TONSL p.Gln511Ter Pathogenic/Likely pathogenic ★★ same type
TONSL p.Glu487Lys Pathogenic/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-arg294trp (accessed [today's date]).

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