Is TONSL p.Arg768Trp (c.2302C>T) pathogenic?

TONSL p.Arg768Trp (c.2302C>T) is classified Uncertain significance in TONSL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-03). AlphaMissense: likely benign (0.1046); Ultra-rare (popmax 0.0946%, amr); Associated with Inborn genetic diseases.

What condition is associated with TONSL p.Arg768Trp (c.2302C>T)?

TONSL p.Arg768Trp (c.2302C>T) is associated with Inborn genetic diseases, spondyloepimetaphyseal dysplasia, sponastrime type (ClinVar).

How common is TONSL p.Arg768Trp (c.2302C>T) in the general population?

TONSL p.Arg768Trp (c.2302C>T) is ultra-rare (popmax 0.0946%, amr) (gnomAD).

What do computational predictors say about TONSL p.Arg768Trp (c.2302C>T)?

AlphaMissense predicts likely benign (score 0.1046) — an in-silico prediction, not a clinical call.

TONSL p.Arg768Trp

c.2302C>T · rs747619822 · VCV1177493

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1046 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0946%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1046	likely benign
REVEL	0.086	moderately benign-leaning
SaProt	LLR -8.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 0.039, phastCons 0.95
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	22.1	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 0.0946% Admixed American · 51/53,886 alleles

Filtering AF 0.0739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0666%

Overall 0.00538% 84/1,561,742 alleles · ultra-rare exomes 60/1,409,560 · genomes 24/152,182 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0946%	1,057
Remaining individualsnot grpmax-eligible	0.0115%	8,686
African / African-American	0.00675%	14,810
European (non-Finnish)	0.00181%	55,261

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.Arg768Trp
Coding: c.2302C>T
MANE Select: NM_013432
dbSNP: rs747619822
Type: single nucleotide variant
Location: chr8:144436131 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 768: 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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: spondyloepimetaphyseal dysplasia, sponastrime type

Similar variants

TONSL p.Arg768Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
TONSL p.Arg768= Likely benign ★ same residue
TONSL c.1891-1G>C Pathogenic/Likely pathogenic ★★ same condition
TONSL p.Arg875Ter Pathogenic/Likely pathogenic ★★ same condition
TONSL p.Arg934Trp Pathogenic ★★ ⚠ same condition
TONSL p.Gln511Ter Pathogenic/Likely pathogenic ★★ same condition
TONSL p.Glu487Lys Pathogenic/Likely pathogenic ★★ ⚠ same condition
TONSL p.Ala1053Ser Uncertain significance ★★ ⚠ same condition

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-arg768trp (accessed [today's date]).

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