Is TOE1 p.Ala452Val (c.1355C>T) pathogenic?

TOE1 p.Ala452Val (c.1355C>T) is classified Uncertain significance in TOE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-06). AlphaMissense: ambiguous (0.3875); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with TOE1 p.Ala452Val (c.1355C>T)?

TOE1 p.Ala452Val (c.1355C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TOE1 p.Ala452Val (c.1355C>T) in the general population?

TOE1 p.Ala452Val (c.1355C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TOE1 p.Ala452Val (c.1355C>T)?

AlphaMissense predicts ambiguous (score 0.3875) — an in-silico prediction, not a clinical call.

TOE1 p.Ala452Val

c.1355C>T · VCV4188812

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3875 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3875	ambiguous
REVEL	0.192	benign-leaning
SaProt	LLR -9.32	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 3,446 bp · p 1.6e-05 · regional, not allelic
Overall
CADD	26.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TOE1
Protein: p.Ala452Val
Coding: c.1355C>T
MANE Select: NM_025077
Type: single nucleotide variant
Location: chr1:45343524 (GRCh38)
Gene constraint: LOEUF 1.225 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.16 · 1 PDB
Residue 452: a UniProt-annotated variant site (in pch7)

Full TOE1 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

TOE1 p.Ala452= Likely benign ★ same residue
TOE1 p.Arg184Cys Uncertain significance ★★ ⚠ same condition
TOE1 p.Arg184His Uncertain significance ★★ ⚠ same condition
TOE1 p.Arg185Gln Uncertain significance ★★ ⚠ same condition
TOE1 p.Arg253Trp Uncertain significance ★★ ⚠ same condition
TOE1 p.Arg293His Uncertain significance ★★ ⚠ same condition
TOE1 p.Arg494His Uncertain significance ★★ ⚠ same condition
TOE1 p.Pro366Leu 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/toe1-p-ala452val (accessed [today's date]).

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