Is TONSL p.Leu456= (c.1368A>G) pathogenic?

TONSL p.Leu456= (c.1368A>G) is classified Benign in TONSL (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Common (popmax 99.7%, sas) — too common for a highly-penetrant pathogenic allele; Associated with spondyloepimetaphyseal dysplasia, sponastrime type.

What condition is associated with TONSL p.Leu456= (c.1368A>G)?

TONSL p.Leu456= (c.1368A>G) is associated with spondyloepimetaphyseal dysplasia, sponastrime type (ClinVar).

How is SPONASTRIME dysplasia inherited?

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

TONSL p.Leu456=

Q: How common is TONSL p.Leu456= (c.1368A>G) in the general population?

TONSL p.Leu456= (c.1368A>G) is common (popmax 99.7%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1368A>G · rs2306383 · VCV1167023

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 99.7%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

spondyloepimetaphyseal dysplasia, sponastrime type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.099	GERP -3.9, phastCons 0.85
Overall
CADD	2.467	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 99.7% South Asian · 90,816/91,052 alleles

Filtering AF 99.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 99.5%

Overall 98.1% 1,581,962/1,612,168 alleles · common exomes 1,436,730/1,459,862 · genomes 145,232/152,306 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	100%	1
South Asiangrpmax	99.7%	1
European (non-Finnish)	99.7%	1
Finnishnot grpmax-eligible	99.6%	1
Middle Eastern	99.1%	1
Ashkenazi Jewishnot grpmax-eligible	98.8%	1
Remaining individualsnot grpmax-eligible	98%	1
Admixed American	89.6%	1
African / African-American	89.4%	1
East Asian	76.1%	1

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu456=
Coding: c.1368A>G
MANE Select: NM_013432
dbSNP: rs2306383
Type: single nucleotide variant
Location: chr8:144440133 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 456: 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-leu456 (accessed [today's date]).

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