Is TONSL p.Asp345Asn (c.1033G>A) pathogenic?

TONSL p.Asp345Asn (c.1033G>A) is classified Uncertain significance in TONSL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-29). AlphaMissense: likely benign (0.0799); Absent from gnomAD v4.1; Associated with spondyloepimetaphyseal dysplasia, sponastrime type.

What condition is associated with TONSL p.Asp345Asn (c.1033G>A)?

TONSL p.Asp345Asn (c.1033G>A) is associated with spondyloepimetaphyseal dysplasia, sponastrime type (ClinVar).

How common is TONSL p.Asp345Asn (c.1033G>A) in the general population?

TONSL p.Asp345Asn (c.1033G>A) is absent from gnomAD v4.1 (gnomAD).

How is SPONASTRIME dysplasia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TONSL p.Asp345Asn (c.1033G>A)?

AlphaMissense predicts likely benign (score 0.0799) — an in-silico prediction, not a clinical call.

TONSL p.Asp345Asn

c.1033G>A · VCV3595447

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0799 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spondyloepimetaphyseal dysplasia, sponastrime type

Computational evidence

Protein change
AlphaMissense	0.0799	likely benign
REVEL	0.034	moderately benign-leaning
SaProt	LLR -6.98	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.7	GERP -3
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	2.422	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TONSL
Protein: p.Asp345Asn
Coding: c.1033G>A
MANE Select: NM_013432
Type: single nucleotide variant
Location: chr8:144440849 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 345: 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

spondyloepimetaphyseal dysplasia, sponastrime type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For SPONASTRIME dysplasia (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

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.Ala1092Val Uncertain significance ★★ ⚠ same condition
TONSL p.Ala192Val Uncertain significance ★★ ⚠ same condition
TONSL p.Ala964Val 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-asp345asn (accessed [today's date]).

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