Is TONSL p.Glu487Lys (c.1459G>A) pathogenic?

TONSL p.Glu487Lys (c.1459G>A) is classified Pathogenic/Likely pathogenic in TONSL (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-09-21). AlphaMissense: likely benign (0.1234); Ultra-rare (popmax 0.0494%, sas); Associated with spondyloepimetaphyseal dysplasia, sponastrime type.

What condition is associated with TONSL p.Glu487Lys (c.1459G>A)?

TONSL p.Glu487Lys (c.1459G>A) is associated with spondyloepimetaphyseal dysplasia, sponastrime type (ClinVar).

How common is TONSL p.Glu487Lys (c.1459G>A) in the general population?

TONSL p.Glu487Lys (c.1459G>A) is ultra-rare (popmax 0.0494%, sas) (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.Glu487Lys (c.1459G>A)?

AlphaMissense predicts likely benign (score 0.1234) — an in-silico prediction, not a clinical call.

TONSL p.Glu487Lys

c.1459G>A · rs563710728 · VCV638062

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1234 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0494%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spondyloepimetaphyseal dysplasia, sponastrime type

Computational evidence

Protein change
AlphaMissense	0.1234	likely benign ⚠ discordant with ClinVar
REVEL	0.167	moderately benign-leaning
SaProt	LLR -9.62	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.22	donor gain · deltas
Pangolin	Δ0.41	gain · loss 0.13 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.9	GERP 2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	22.9	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 0.0494% South Asian · 43/87,130 alleles

Filtering AF 0.0376% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0335%

Overall 0.00409% 58/1,419,696 alleles · ultra-rare exomes 55/1,267,330 · genomes 3/152,366 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0494%	2,026
Middle Eastern	0.0177%	5,660
Remaining individualsnot grpmax-eligible	0.00891%	11,224
European (non-Finnish)	0.000896%	111,604

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.Glu487Lys
Coding: c.1459G>A
MANE Select: NM_013432
dbSNP: rs563710728
Type: single nucleotide variant
Location: chr8:144440042 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 487: 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.Ala1092Val Uncertain significance ★★ ⚠ same condition
TONSL p.Ala192Val Uncertain significance ★★ ⚠ same condition
TONSL p.Ala964Val Uncertain significance ★★ same condition
TONSL p.Arg1116His 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-glu487lys (accessed [today's date]).

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