Is TONSL p.Ala1184Val (c.3551C>T) pathogenic?

TONSL p.Ala1184Val (c.3551C>T) is classified Conflicting classifications of pathogenicity in TONSL (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-25). AlphaMissense: likely benign (0.1219); Rare (popmax 0.814%, sas); Associated with Inborn genetic diseases.

What condition is associated with TONSL p.Ala1184Val (c.3551C>T)?

TONSL p.Ala1184Val (c.3551C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TONSL p.Ala1184Val (c.3551C>T) in the general population?

TONSL p.Ala1184Val (c.3551C>T) is rare (popmax 0.814%, sas) (gnomAD).

What do computational predictors say about TONSL p.Ala1184Val (c.3551C>T)?

AlphaMissense predicts likely benign (score 0.1219) — an in-silico prediction, not a clinical call.

TONSL p.Ala1184Val

c.3551C>T · rs372316501 · VCV1618416

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1219 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.814%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1219	likely benign
REVEL	0.233	benign-leaning
SaProt	LLR -11.36	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.4	GERP 0.68, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	23.9	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 0.814% South Asian · 741/91,072 alleles

Filtering AF 0.765% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.746%

Overall 0.0488% 787/1,613,362 alleles · rare exomes 750/1,460,990 · genomes 37/152,372 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.814%	123
Remaining individualsnot grpmax-eligible	0.0656%	1,524
Admixed American	0.00167%	59,996
African / African-American	0.00133%	75,062
European (non-Finnish)	0.000254%	393,303

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.Ala1184Val
Coding: c.3551C>T
MANE Select: NM_013432
dbSNP: rs372316501
Type: single nucleotide variant
Location: chr8:144433596 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 1184: 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

Similar variants

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.Ala232Val 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-ala1184val (accessed [today's date]).

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