Is TONSL p.Glu494Lys (c.1480G>A) pathogenic?

TONSL p.Glu494Lys (c.1480G>A) is classified Conflicting classifications of pathogenicity in TONSL (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2022-10-04). AlphaMissense: likely benign (0.1062); Very rare (popmax 0.0015%, afr); Associated with spondyloepimetaphyseal dysplasia, sponastrime type.

What condition is associated with TONSL p.Glu494Lys (c.1480G>A)?

TONSL p.Glu494Lys (c.1480G>A) is associated with spondyloepimetaphyseal dysplasia, sponastrime type (ClinVar).

How common is TONSL p.Glu494Lys (c.1480G>A) in the general population?

TONSL p.Glu494Lys (c.1480G>A) is very rare (popmax 0.0015%, afr) (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.Glu494Lys (c.1480G>A)?

AlphaMissense predicts likely benign (score 0.1062) — an in-silico prediction, not a clinical call.

TONSL p.Glu494Lys

c.1480G>A · rs775551492 · VCV638065

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1062 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0015%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spondyloepimetaphyseal dysplasia, sponastrime type

Computational evidence

Protein change
AlphaMissense	0.1062	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -10.25	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	Δ0.29	donor loss · deltas
Pangolin	Δ0.72	loss · gain 0.24 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	26.4	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 0.0015% African / African-American · 1/66,634 alleles

Filtering AF 0.000273% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000179%

Overall 0.000674% 8/1,186,130 alleles · very rare exomes 7/1,033,904 · genomes 1/152,226 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0015%	66,634
South Asian	0.00121%	82,516
European (non-Finnish)	0.000758%	131,914

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.Glu494Lys
Coding: c.1480G>A
MANE Select: NM_013432
dbSNP: rs775551492
Type: single nucleotide variant
Location: chr8:144440021 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 494: the 'disordered' region; 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; uncertain significance)

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-glu494lys (accessed [today's date]).

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