Is TONSL p.Ala478Glu (c.1433C>A) pathogenic?

TONSL p.Ala478Glu (c.1433C>A) is classified Uncertain significance in TONSL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-14). AlphaMissense: likely benign (0.0936); Ultra-rare (popmax 0.0501%, mid); Associated with Inborn genetic diseases.

What condition is associated with TONSL p.Ala478Glu (c.1433C>A)?

TONSL p.Ala478Glu (c.1433C>A) is associated with Inborn genetic diseases (ClinVar).

How common is TONSL p.Ala478Glu (c.1433C>A) in the general population?

TONSL p.Ala478Glu (c.1433C>A) is ultra-rare (popmax 0.0501%, mid) (gnomAD).

What do computational predictors say about TONSL p.Ala478Glu (c.1433C>A)?

AlphaMissense predicts likely benign (score 0.0936) — an in-silico prediction, not a clinical call.

TONSL p.Ala478Glu

c.1433C>A · rs137885184 · VCV1347979

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0936 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0501%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0936	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -5.23	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 -3	GERP -2.9
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	0.021	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 0.0501% Middle Eastern · 3/5,988 alleles

Filtering AF 0.0136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00727%

Overall 0.00228% 36/1,578,310 alleles · ultra-rare exomes 36/1,426,072 · genomes 0/152,238 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0501%	1,996
Remaining individualsnot grpmax-eligible	0.00816%	12,255
African / African-American	0.00269%	37,108
European (non-Finnish)	0.00218%	45,975
South Asian	0.00111%	90,302

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.Ala478Glu
Coding: c.1433C>A
MANE Select: NM_013432
dbSNP: rs137885184
Type: single nucleotide variant
Location: chr8:144440068 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 478: the 'disordered' region; 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

Disease context

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

Similar variants

TONSL p.Ala478= Likely benign ★★ same residue
TONSL p.Ala478Val 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-ala478glu (accessed [today's date]).

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