Is TONSL p.Ala232Val (c.695C>T) pathogenic?

TONSL p.Ala232Val (c.695C>T) is classified Uncertain significance in TONSL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-03-19). AlphaMissense: likely pathogenic (0.8119); Very rare (popmax 0.00564%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TONSL p.Ala232Val (c.695C>T)?

TONSL p.Ala232Val (c.695C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TONSL p.Ala232Val (c.695C>T) in the general population?

TONSL p.Ala232Val (c.695C>T) is very rare (popmax 0.00564%, nfe) (gnomAD).

What do computational predictors say about TONSL p.Ala232Val (c.695C>T)?

AlphaMissense predicts likely pathogenic (score 0.8119) — an in-silico prediction, not a clinical call.

TONSL p.Ala232Val

c.695C>T · rs368498512 · VCV2161292

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8119 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00564%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8119	likely pathogenic · top 10% in TONSL
REVEL	0.458	indeterminate
SaProt	LLR -13.36	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00564% European (non-Finnish) · 66/1,169,430 alleles

Filtering AF 0.00455% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00415%

Overall 0.00463% 74/1,598,270 alleles · very rare exomes 68/1,446,034 · genomes 6/152,236 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00564%	17,719
African / African-American	0.00402%	24,894
Remaining individualsnot grpmax-eligible	0.00324%	30,881
East Asian	0.00225%	44,520
Admixed American	0.00168%	59,500
South Asian	0.0011%	90,552

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.Ala232Val
Coding: c.695C>T
MANE Select: NM_013432
dbSNP: rs368498512
Type: single nucleotide variant
Location: chr8:144442296 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 232: 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

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

Similar variants

TONSL p.Ala232= Likely benign ★★ same residue
TONSL p.Ala1053Ser Uncertain significance ★★ ⚠ same condition
TONSL p.Ala1065Ser Uncertain significance ★★ ⚠ same condition
TONSL p.Ala1093Ser Uncertain significance ★★ ⚠ same condition
TONSL p.Ala1200Thr Uncertain significance ★★ ⚠ same condition
TONSL p.Ala215Thr Uncertain significance ★★ ⚠ same condition
TONSL p.Ala331Thr Uncertain significance ★★ ⚠ same condition
TONSL p.Ala478Glu 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-ala232val (accessed [today's date]).

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