Is TONSL p.Gln88Pro (c.263A>C) pathogenic?

TONSL p.Gln88Pro (c.263A>C) is classified Uncertain significance in TONSL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-03). AlphaMissense: ambiguous (0.3663); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with TONSL p.Gln88Pro (c.263A>C)?

TONSL p.Gln88Pro (c.263A>C) is associated with Inborn genetic diseases (ClinVar).

How common is TONSL p.Gln88Pro (c.263A>C) in the general population?

TONSL p.Gln88Pro (c.263A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TONSL p.Gln88Pro (c.263A>C)?

AlphaMissense predicts ambiguous (score 0.3663) — an in-silico prediction, not a clinical call.

TONSL p.Gln88Pro

c.263A>C · VCV3328033

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3663 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3663	ambiguous
REVEL	0.375	indeterminate
SaProt	LLR -12.12	damaging
Splicing
SpliceAI	Δ0.32	donor loss, 1 bp away · masked 0 · deltas
Pangolin	Δ0.51	loss · gain 0.05 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 1.9	GERP 0.76, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	23.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TONSL
Protein: p.Gln88Pro
Coding: c.263A>C
MANE Select: NM_013432
Type: single nucleotide variant
Location: chr8:144443883 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB

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.Gln88Ter Likely pathogenic ★ same residue
TONSL p.Gln88His Uncertain significance ★ ⚠ 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-gln88pro (accessed [today's date]).

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