Is TONSL p.Ala893Thr (c.2677G>A) pathogenic?

TONSL p.Ala893Thr (c.2677G>A) is classified Conflicting classifications of pathogenicity in TONSL (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.0766); Rare (popmax 0.508%, afr); Associated with Inborn genetic diseases.

What condition is associated with TONSL p.Ala893Thr (c.2677G>A)?

TONSL p.Ala893Thr (c.2677G>A) is associated with Inborn genetic diseases (ClinVar).

How common is TONSL p.Ala893Thr (c.2677G>A) in the general population?

TONSL p.Ala893Thr (c.2677G>A) is rare (popmax 0.508%, afr) (gnomAD).

What do computational predictors say about TONSL p.Ala893Thr (c.2677G>A)?

AlphaMissense predicts likely benign (score 0.0766) — an in-silico prediction, not a clinical call.

TONSL p.Ala893Thr

c.2677G>A · rs148167168 · VCV1557300

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0766 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.508%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0766	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -6.97	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 -0.076	GERP -2.2
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	7.429	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 0.508% African / African-American · 381/75,036 alleles

Filtering AF 0.466% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.449%

Overall 0.0409% 660/1,612,836 alleles · rare exomes 407/1,460,548 · genomes 253/152,288 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.508%	197
Finnishnot grpmax-eligible	0.272%	368
Admixed American	0.0666%	1,501
Remaining individualsnot grpmax-eligible	0.0576%	1,736
Middle Eastern	0.033%	3,030
European (non-Finnish)	0.00254%	39,331

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.Ala893Thr
Coding: c.2677G>A
MANE Select: NM_013432
dbSNP: rs148167168
Type: single nucleotide variant
Location: chr8:144435756 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 893: 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)

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-ala893thr (accessed [today's date]).

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