Is TONSL p.Ser126Trp (c.377C>G) pathogenic?

TONSL p.Ser126Trp (c.377C>G) is classified Uncertain significance in TONSL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-19). AlphaMissense: likely benign (0.2548); Very rare (popmax 0.00958%, afr); Associated with Inborn genetic diseases.

What condition is associated with TONSL p.Ser126Trp (c.377C>G)?

TONSL p.Ser126Trp (c.377C>G) is associated with Inborn genetic diseases (ClinVar).

How common is TONSL p.Ser126Trp (c.377C>G) in the general population?

TONSL p.Ser126Trp (c.377C>G) is very rare (popmax 0.00958%, afr) (gnomAD).

What do computational predictors say about TONSL p.Ser126Trp (c.377C>G)?

AlphaMissense predicts likely benign (score 0.2548) — an in-silico prediction, not a clinical call.

TONSL p.Ser126Trp

c.377C>G · VCV4633407

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2548 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00958%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2548	likely benign
REVEL	0.578	indeterminate
SaProt	LLR -12.14	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.5	GERP 0.23, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	25.0	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 0.00958% African / African-American · 7/73,052 alleles

Filtering AF 0.00447% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00315%

Overall 0.000516% 8/1,550,650 alleles · very rare exomes 4/1,398,420 · genomes 4/152,230 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00958%	10,436
Admixed American	0.00196%	50,990

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.Ser126Trp
Coding: c.377C>G
MANE Select: NM_013432
Type: single nucleotide variant
Location: chr8:144443209 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 126: a UniProt-annotated variant site (in semdsp; disease phenotype includes immunologic and hematologic abnormalities)

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.Ser126Leu Uncertain significance ★ ⚠ same residue
TONSL p.Ser126= 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-ser126trp (accessed [today's date]).

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