Is TONSL p.Ala622fs (c.1864dup) pathogenic?

TONSL p.Ala622fs (c.1864dup) is classified Pathogenic in TONSL (ClinVar, Single submitter, 2 submitters; last evaluated 2024-11-11). Very rare (popmax 0.00167%, amr); Associated with spondyloepimetaphyseal dysplasia, sponastrime type.

What condition is associated with TONSL p.Ala622fs (c.1864dup)?

TONSL p.Ala622fs (c.1864dup) is associated with spondyloepimetaphyseal dysplasia, sponastrime type (ClinVar).

How common is TONSL p.Ala622fs (c.1864dup) in the general population?

TONSL p.Ala622fs (c.1864dup) is very rare (popmax 0.00167%, amr) (gnomAD).

How is SPONASTRIME dysplasia inherited?

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

TONSL p.Ala622fs

c.1864dup · rs762903420 · VCV982174

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

spondyloepimetaphyseal dysplasia, sponastrime type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 15 of 26
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,994 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000434% 7/1,611,066 alleles · very rare exomes 7/1,458,778 · genomes 0/152,288 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,994
European (non-Finnish)	0.000509%	196,617

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.Ala622fs
Coding: c.1864dup
MANE Select: NM_013432
dbSNP: rs762903420
Type: Duplication
Location: chr8:144436782 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 622: 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 p.Leu225fs Pathogenic/Likely pathogenic ★★ same condition
TONSL p.Ala622= Likely benign ★★ same residue
TONSL p.Leu1324fs Likely pathogenic ★ same condition
TONSL p.Ala622Pro Uncertain significance ★ ⚠ same residue
TONSL p.Ala622Thr Uncertain significance ★ ⚠ same residue
TONSL p.Arg1266fs Likely pathogenic same condition
TONSL p.Gln1033fs Likely pathogenic same condition
TONSL c.1891-1G>C Pathogenic/Likely pathogenic ★★ 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-ala622fs (accessed [today's date]).

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