Is TONSL p.Arg934Trp (c.2800C>T) pathogenic?

TONSL p.Arg934Trp (c.2800C>T) is classified Pathogenic in TONSL (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-06). AlphaMissense: likely benign (0.305); Very rare (popmax 0.00244%, eas); Associated with spondyloepimetaphyseal dysplasia, sponastrime type.

What condition is associated with TONSL p.Arg934Trp (c.2800C>T)?

TONSL p.Arg934Trp (c.2800C>T) is associated with spondyloepimetaphyseal dysplasia, sponastrime type (ClinVar).

How common is TONSL p.Arg934Trp (c.2800C>T) in the general population?

TONSL p.Arg934Trp (c.2800C>T) is very rare (popmax 0.00244%, eas) (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.Arg934Trp (c.2800C>T)?

AlphaMissense predicts likely benign (score 0.305) — an in-silico prediction, not a clinical call.

TONSL p.Arg934Trp

c.2800C>T · rs755575416 · VCV638059

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.305 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00244%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

spondyloepimetaphyseal dysplasia, sponastrime type

Computational evidence

Protein change
AlphaMissense	0.305	likely benign ⚠ discordant with ClinVar
REVEL	0.456	indeterminate
SaProt	LLR -14.67	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 5	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	26.2	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 0.00244% East Asian · 1/41,024 alleles

Filtering AF 0.00126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00107%

Overall 0.00155% 24/1,551,028 alleles · very rare exomes 22/1,398,822 · genomes 2/152,206 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00244%	41,024
European (non-Finnish)	0.00192%	52,137
South Asian	0.00119%	84,370

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.Arg934Trp
Coding: c.2800C>T
MANE Select: NM_013432
dbSNP: rs755575416
Type: single nucleotide variant
Location: chr8:144435526 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 934: 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); a UniProt-annotated variant site (in semdsp; decreased function in double-strand break repair via homologous recombination)

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.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
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-arg934trp (accessed [today's date]).

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