Is TONSL p.Ala478= (c.1434G>A) pathogenic?

TONSL p.Ala478= (c.1434G>A) is classified Likely benign in TONSL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-16). Very rare (popmax 0.00336%, amr); Associated with Inborn genetic diseases.

What condition is associated with TONSL p.Ala478= (c.1434G>A)?

TONSL p.Ala478= (c.1434G>A) is associated with Inborn genetic diseases (ClinVar).

How common is TONSL p.Ala478= (c.1434G>A) in the general population?

TONSL p.Ala478= (c.1434G>A) is very rare (popmax 0.00336%, amr) (gnomAD).

TONSL p.Ala478=

c.1434G>A · VCV3633602

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00336%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.1	GERP -3
Overall
CADD	0.923	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00336% Admixed American · 2/59,610 alleles

Filtering AF 0.000979% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000808%

Overall 0.00158% 25/1,578,468 alleles · very rare exomes 25/1,426,186 · genomes 0/152,282 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00336%	29,805
South Asian	0.00332%	30,099
East Asian	0.00224%	44,684
European (non-Finnish)	0.00157%	63,851
African / African-American	0.00135%	74,280

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.Ala478=
Coding: c.1434G>A
MANE Select: NM_013432
Type: single nucleotide variant
Location: chr8:144440067 (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.Ala478Glu Uncertain significance ★★ ⚠ 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-ala478 (accessed [today's date]).

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