Is TONSL p.Gly404Ser (c.1210G>A) pathogenic?

TONSL p.Gly404Ser (c.1210G>A) is classified Uncertain significance in TONSL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-03). AlphaMissense: likely benign (0.2401); Ultra-rare (popmax 0.0167%, amr); Associated with Inborn genetic diseases.

What condition is associated with TONSL p.Gly404Ser (c.1210G>A)?

TONSL p.Gly404Ser (c.1210G>A) is associated with Inborn genetic diseases (ClinVar).

How common is TONSL p.Gly404Ser (c.1210G>A) in the general population?

TONSL p.Gly404Ser (c.1210G>A) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about TONSL p.Gly404Ser (c.1210G>A)?

AlphaMissense predicts likely benign (score 0.2401) — an in-silico prediction, not a clinical call.

TONSL p.Gly404Ser

c.1210G>A · rs780347294 · VCV1921151

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2401 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2401	likely benign
REVEL	0.305	indeterminate
SaProt	LLR -10.10	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	23.5	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 0.0167% Admixed American · 10/59,854 alleles

Filtering AF 0.00902% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00683%

Overall 0.00187% 30/1,608,564 alleles · ultra-rare exomes 29/1,456,348 · genomes 1/152,216 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,985
Finnishnot grpmax-eligible	0.0112%	8,896
East Asian	0.00223%	44,768
Remaining individualsnot grpmax-eligible	0.00161%	62,222
African / African-American	0.00134%	74,854
South Asian	0.0011%	90,940
European (non-Finnish)	0.000765%	130,797

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.Gly404Ser
Coding: c.1210G>A
MANE Select: NM_013432
dbSNP: rs780347294
Type: single nucleotide variant
Location: chr8:144440431 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 404: 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.Gly404= 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
TONSL p.Ala331Thr 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-gly404ser (accessed [today's date]).

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