Is TONSL p.Arg789Trp (c.2365C>T) pathogenic?

TONSL p.Arg789Trp (c.2365C>T) is classified Uncertain significance in TONSL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-16). AlphaMissense: likely benign (0.0886); Ultra-rare (popmax 0.0334%, mid).

How common is TONSL p.Arg789Trp (c.2365C>T) in the general population?

TONSL p.Arg789Trp (c.2365C>T) is ultra-rare (popmax 0.0334%, mid) (gnomAD).

What do computational predictors say about TONSL p.Arg789Trp (c.2365C>T)?

AlphaMissense predicts likely benign (score 0.0886) — an in-silico prediction, not a clinical call.

TONSL p.Arg789Trp

c.2365C>T · rs751594566 · VCV1415335

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0886 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0886	likely benign
REVEL	0.013	strongly benign-leaning
SaProt	LLR -7.94	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.7	GERP -1.1, phastCons 0.023
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	16.03	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0334% Middle Eastern · 2/5,988 alleles

Filtering AF 0.0143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.014% 220/1,569,764 alleles · ultra-rare exomes 203/1,417,586 · genomes 17/152,178 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0334%	2,994
Admixed American	0.0215%	4,641
Remaining individualsnot grpmax-eligible	0.018%	5,551
European (non-Finnish)	0.0162%	6,163
South Asian	0.00454%	22,010
African / African-American	0.0027%	37,050

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.Arg789Trp
Coding: c.2365C>T
MANE Select: NM_013432
dbSNP: rs751594566
Type: single nucleotide variant
Location: chr8:144436068 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 789: the 'disordered' region; 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.Arg789Gln 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
TONSL c.2775+5G>T 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-arg789trp (accessed [today's date]).

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