Is TONSL p.Ala964Val (c.2891C>T) pathogenic?

TONSL p.Ala964Val (c.2891C>T) is classified Uncertain significance in TONSL (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-08-31). AlphaMissense: ambiguous (0.4062); Ultra-rare (popmax 0.0199%, mid); Associated with Inborn genetic diseases.

What condition is associated with TONSL p.Ala964Val (c.2891C>T)?

TONSL p.Ala964Val (c.2891C>T) is associated with Inborn genetic diseases, spondyloepimetaphyseal dysplasia, sponastrime type (ClinVar).

How common is TONSL p.Ala964Val (c.2891C>T) in the general population?

TONSL p.Ala964Val (c.2891C>T) is ultra-rare (popmax 0.0199%, mid) (gnomAD).

What do computational predictors say about TONSL p.Ala964Val (c.2891C>T)?

AlphaMissense predicts ambiguous (score 0.4062) — an in-silico prediction, not a clinical call.

TONSL p.Ala964Val

c.2891C>T · rs778431357 · VCV1435174

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4062 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0199%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4062	ambiguous
REVEL	0.319	indeterminate
SaProt	LLR -7.23	tolerated
Splicing
SpliceAI	Δ0.29	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 8.6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	34.0	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 0.0199% Middle Eastern · 1/5,024 alleles

Filtering AF 0.00425% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00386%

Overall 0.00578% 91/1,573,530 alleles · ultra-rare exomes 79/1,421,292 · genomes 12/152,238 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.039%	2,563
Middle Easterngrpmax	0.0199%	5,024
European (non-Finnish)	0.00534%	18,715
South Asian	0.00458%	21,849
African / African-American	0.00136%	73,766

Finnish 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.Ala964Val
Coding: c.2891C>T
MANE Select: NM_013432
dbSNP: rs778431357
Type: single nucleotide variant
Location: chr8:144435132 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 964: 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)

Full TONSL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: spondyloepimetaphyseal dysplasia, sponastrime type

Similar variants

TONSL p.Ala964= Likely benign ★ same residue
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.Ala1053Ser Uncertain significance ★★ ⚠ same condition
TONSL p.Ala1065Ser 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-ala964val (accessed [today's date]).

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