Is TONSL p.Ala714Val (c.2141C>T) pathogenic?

TONSL p.Ala714Val (c.2141C>T) is classified Benign in TONSL (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0891); Common (popmax 57.9%, sas) — too common for a highly-penetrant pathogenic allele; Associated with spondyloepimetaphyseal dysplasia, sponastrime type.

What condition is associated with TONSL p.Ala714Val (c.2141C>T)?

TONSL p.Ala714Val (c.2141C>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.

What do computational predictors say about TONSL p.Ala714Val (c.2141C>T)?

AlphaMissense predicts likely benign (score 0.0891) — an in-silico prediction, not a clinical call.

TONSL p.Ala714Val

Q: How common is TONSL p.Ala714Val (c.2141C>T) in the general population?

TONSL p.Ala714Val (c.2141C>T) is common (popmax 57.9%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2141C>T · rs7830832 · VCV1167021

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0891 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 57.9%, sas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spondyloepimetaphyseal dysplasia, sponastrime type

Computational evidence

Protein change
AlphaMissense	0.0891	likely benign
REVEL	0.023	moderately benign-leaning
SaProt	LLR -7.18	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.66	GERP -2.2, phastCons 0.17
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	14.54	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 57.9% South Asian · 44,235/76,350 alleles

Filtering AF 57.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 57.3%

Overall 46.4% 697,855/1,505,036 alleles · common exomes 633,255/1,353,124 · genomes 64,600/151,912 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	57.9%	2
Amishnot grpmax-eligible	51.4%	2
Finnishnot grpmax-eligible	47.8%	2
European (non-Finnish)	47.3%	2
Remaining individualsnot grpmax-eligible	45%	2
Admixed American	41.8%	2
East Asian	37%	3
Middle Eastern	36.8%	3
African / African-American	33.8%	3
Ashkenazi Jewishnot grpmax-eligible	32.2%	3

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.Ala714Val
Coding: c.2141C>T
MANE Select: NM_013432
dbSNP: rs7830832
Type: single nucleotide variant
Location: chr8:144436292 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 714: 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; disease phenotype includes primary aphakia and absent pupils); a UniProt-annotated variant site (in)

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-ala714val (accessed [today's date]).

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