Is TONSL p.Arg768Gln (c.2303G>A) pathogenic?

TONSL p.Arg768Gln (c.2303G>A) is classified Conflicting classifications of pathogenicity in TONSL (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-02). AlphaMissense: likely benign (0.065); Very rare (popmax 0.00457%, sas); Associated with Inborn genetic diseases.

What condition is associated with TONSL p.Arg768Gln (c.2303G>A)?

TONSL p.Arg768Gln (c.2303G>A) is associated with Inborn genetic diseases (ClinVar).

How common is TONSL p.Arg768Gln (c.2303G>A) in the general population?

TONSL p.Arg768Gln (c.2303G>A) is very rare (popmax 0.00457%, sas) (gnomAD).

What do computational predictors say about TONSL p.Arg768Gln (c.2303G>A)?

AlphaMissense predicts likely benign (score 0.065) — an in-silico prediction, not a clinical call.

TONSL p.Arg768Gln

c.2303G>A · rs779585131 · VCV1475763

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.065 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00457%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.065	likely benign
REVEL	0.03	moderately benign-leaning
SaProt	LLR -6.70	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.32	donor gain · deltas
Constraint at this position
Conservation	phyloP -1.1	GERP -2.3
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	7.909	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 0.00457% South Asian · 4/87,580 alleles

Filtering AF 0.00147% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000919%

Overall 0.000897% 14/1,561,478 alleles · very rare exomes 13/1,409,306 · genomes 1/152,172 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00457%	21,895
European (non-Finnish)	0.000862%	116,040

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.Arg768Gln
Coding: c.2303G>A
MANE Select: NM_013432
dbSNP: rs779585131
Type: single nucleotide variant
Location: chr8:144436130 (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

Similar variants

TONSL p.Arg768Trp Uncertain significance ★★ ⚠ same residue
TONSL p.Arg768= Likely benign ★ same residue
TONSL p.Ala1053Ser Uncertain significance ★★ ⚠ same condition
TONSL p.Ala1065Ser Uncertain significance ★★ ⚠ same condition
TONSL p.Ala1093Ser Uncertain significance ★★ ⚠ same condition
TONSL p.Ala1200Thr Uncertain significance ★★ ⚠ same condition
TONSL p.Ala215Thr Uncertain significance ★★ ⚠ same condition
TONSL p.Ala232Val 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-arg768gln (accessed [today's date]).

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