Is TONSL p.Ala1166Val (c.3497C>T) pathogenic?

TONSL p.Ala1166Val (c.3497C>T) is classified Uncertain significance in TONSL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-31). AlphaMissense: ambiguous (0.51); Ultra-rare (popmax 0.011%, sas).

How common is TONSL p.Ala1166Val (c.3497C>T) in the general population?

TONSL p.Ala1166Val (c.3497C>T) is ultra-rare (popmax 0.011%, sas) (gnomAD).

What do computational predictors say about TONSL p.Ala1166Val (c.3497C>T)?

AlphaMissense predicts ambiguous (score 0.51) — an in-silico prediction, not a clinical call.

TONSL p.Ala1166Val

c.3497C>T · rs2537479885 · VCV2417698

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.51 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.51	ambiguous
REVEL	0.239	benign-leaning
SaProt	LLR -7.14	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	Δ0.55	donor gain · deltas
Pangolin	Δ0.35	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.8, 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 0.011% South Asian · 10/91,078 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.000806% 13/1,613,320 alleles · ultra-rare exomes 13/1,460,952 · genomes 0/152,368 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,108
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,596
African / African-American	0.00133%	75,066
European (non-Finnish)	8.47e-05%	1,179,974

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.Ala1166Val
Coding: c.3497C>T
MANE Select: NM_013432
dbSNP: rs2537479885
Type: single nucleotide variant
Location: chr8:144433650 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 1166: 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

Similar variants

TONSL p.Ala1166= Likely benign ★★ same residue
TONSL c.1891-1G>C Pathogenic/Likely pathogenic ★★ same type
TONSL p.Arg875Ter Pathogenic/Likely pathogenic ★★ same type
TONSL p.Arg934Trp Pathogenic ★★ ⚠ same type
TONSL p.Gln177Ter Pathogenic/Likely pathogenic ★★ same type
TONSL p.Gln511Ter Pathogenic/Likely pathogenic ★★ same type
TONSL p.Glu487Lys Pathogenic/Likely pathogenic ★★ ⚠ same type
TONSL c.2775+5G>T Uncertain significance ★★ same type

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-ala1166val (accessed [today's date]).

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