Is TONSL p.Ala421= (c.1263C>T) pathogenic?

TONSL p.Ala421= (c.1263C>T) is classified Benign in TONSL (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Common (popmax 66.3%, mid) — too common for a highly-penetrant pathogenic allele; Associated with spondyloepimetaphyseal dysplasia, sponastrime type.

What condition is associated with TONSL p.Ala421= (c.1263C>T)?

TONSL p.Ala421= (c.1263C>T) 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.Ala421=

Q: How common is TONSL p.Ala421= (c.1263C>T) in the general population?

TONSL p.Ala421= (c.1263C>T) is common (popmax 66.3%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1263C>T · rs2229313 · VCV1167024

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 66.3%, mid) — 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 1.3	GERP -3.9, phastCons 1
Overall
CADD	4.662	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 66.3% Middle Eastern · 3,962/5,976 alleles

Filtering AF 64.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 63.9%

Overall 56% 897,341/1,603,264 alleles · common exomes 821,141/1,451,204 · genomes 76,200/152,060 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	67.8%	1
Middle Easterngrpmax	66.3%	2
European (non-Finnish)	59.2%	2
Remaining individualsnot grpmax-eligible	56.7%	2
Amishnot grpmax-eligible	54.3%	2
Finnishnot grpmax-eligible	51.8%	2
Admixed American	50.7%	2
South Asian	42.9%	2
East Asian	36.7%	3
African / African-American	34.3%	3

Ashkenazi Jewish 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.Ala421=
Coding: c.1263C>T
MANE Select: NM_013432
dbSNP: rs2229313
Type: single nucleotide variant
Location: chr8:144440378 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 421: 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-ala421 (accessed [today's date]).

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