Is TONSL p.Ala280Thr (c.838G>A) pathogenic?

TONSL p.Ala280Thr (c.838G>A) is classified Uncertain significance in TONSL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-11). AlphaMissense: likely benign (0.0785); Ultra-rare (popmax 0.0224%, nfe).

How common is TONSL p.Ala280Thr (c.838G>A) in the general population?

TONSL p.Ala280Thr (c.838G>A) is ultra-rare (popmax 0.0224%, nfe) (gnomAD).

What do computational predictors say about TONSL p.Ala280Thr (c.838G>A)?

AlphaMissense predicts likely benign (score 0.0785) — an in-silico prediction, not a clinical call.

TONSL p.Ala280Thr

c.838G>A · rs566845306 · VCV1365217

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0785 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0224%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0785	likely benign
REVEL	0.177	moderately benign-leaning
SaProt	LLR -7.42	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.74 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.4	GERP 0.39, phastCons 0.003
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	13.88	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 0.0224% European (non-Finnish) · 264/1,179,928 alleles

Filtering AF 0.0201% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0193%

Overall 0.0173% 279/1,612,846 alleles · ultra-rare exomes 256/1,460,524 · genomes 23/152,322 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0224%	4,469
Remaining individualsnot grpmax-eligible	0.016%	6,248
African / African-American	0.00666%	15,012

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.Ala280Thr
Coding: c.838G>A
MANE Select: NM_013432
dbSNP: rs566845306
Type: single nucleotide variant
Location: chr8:144442064 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 280: 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 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
TONSL p.Ala1053Ser 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-ala280thr (accessed [today's date]).

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