Is TONSL p.Arg1349Ser (c.4047G>T) pathogenic?

TONSL p.Arg1349Ser (c.4047G>T) is classified Uncertain significance in TONSL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.285); Rare (popmax 0.13%, amr); Associated with Inborn genetic diseases.

What condition is associated with TONSL p.Arg1349Ser (c.4047G>T)?

TONSL p.Arg1349Ser (c.4047G>T) is associated with Inborn genetic diseases, spondyloepimetaphyseal dysplasia, sponastrime type (ClinVar).

How common is TONSL p.Arg1349Ser (c.4047G>T) in the general population?

TONSL p.Arg1349Ser (c.4047G>T) is rare (popmax 0.13%, amr) (gnomAD).

What do computational predictors say about TONSL p.Arg1349Ser (c.4047G>T)?

AlphaMissense predicts likely benign (score 0.285) — an in-silico prediction, not a clinical call.

TONSL p.Arg1349Ser

c.4047G>T · rs561356988 · VCV1421877

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.285 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.13%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.285	likely benign
REVEL	0.178	moderately benign-leaning
SaProt	LLR -8.97	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 -2	GERP -3.5
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	11.84	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 0.13% Admixed American · 66/50,708 alleles

Filtering AF 0.105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0958%

Overall 0.00573% 88/1,535,434 alleles · rare exomes 46/1,383,064 · genomes 42/152,370 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.13%	768
Remaining individualsnot grpmax-eligible	0.0301%	3,317
African / African-American	0.00413%	24,239
European (non-Finnish)	8.74e-05%	1,144,266

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.Arg1349Ser
Coding: c.4047G>T
MANE Select: NM_013432
dbSNP: rs561356988
Type: single nucleotide variant
Location: chr8:144429233 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 1349: a UniProt-annotated variant site (in semdsp; disease phenotype includes immunologic and hematologic abnormalities); a UniProt-annotated variant site (in semdsp); a UniProt-annotated variant site (in semdsp; disease phenotype includes primary aphakia and absent pupils)

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

Also linked: spondyloepimetaphyseal dysplasia, sponastrime type

Similar variants

TONSL p.Arg1349Lys Uncertain significance ★ ⚠ same residue
TONSL p.Arg1349= Likely benign ★ same residue
TONSL c.1891-1G>C Pathogenic/Likely pathogenic ★★ same condition
TONSL p.Arg875Ter Pathogenic/Likely pathogenic ★★ same condition
TONSL p.Arg934Trp Pathogenic ★★ ⚠ same condition
TONSL p.Gln511Ter Pathogenic/Likely pathogenic ★★ same condition
TONSL p.Glu487Lys Pathogenic/Likely pathogenic ★★ ⚠ same condition
TONSL p.Ala1053Ser 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-arg1349ser (accessed [today's date]).

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