Is TOE1 p.Gly145Ser (c.433G>A) pathogenic?

TOE1 p.Gly145Ser (c.433G>A) is classified Uncertain significance in TOE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-22). AlphaMissense: ambiguous (0.4169); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TOE1 p.Gly145Ser (c.433G>A)?

TOE1 p.Gly145Ser (c.433G>A) is associated with Inborn genetic diseases (ClinVar).

How common is TOE1 p.Gly145Ser (c.433G>A) in the general population?

TOE1 p.Gly145Ser (c.433G>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about TOE1 p.Gly145Ser (c.433G>A)?

AlphaMissense predicts ambiguous (score 0.4169) — an in-silico prediction, not a clinical call.

TOE1 p.Gly145Ser

c.433G>A · rs2524788702 · VCV2284973

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4169 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4169	ambiguous
REVEL	0.662	pathogenic-leaning
SaProt	LLR -9.97	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 3,446 bp · p 1.6e-05 · regional, not allelic
Overall
CADD	29.7	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 8.48e-05% European (non-Finnish) · 1/1,179,916 alleles

Overall 6.2e-05% 1/1,614,038 alleles · very rare exomes 1/1,461,730 · genomes 0/152,308 · joint denominator

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: TOE1
Protein: p.Gly145Ser
Coding: c.433G>A
MANE Select: NM_025077
dbSNP: rs2524788702
Type: single nucleotide variant
Location: chr1:45342048 (GRCh38)
Gene constraint: LOEUF 1.225 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.16 · 1 PDB

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

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TOE1 p.Arg293His Uncertain significance ★★ ⚠ same condition
TOE1 p.Arg494His Uncertain significance ★★ ⚠ same condition
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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-gly145ser (accessed [today's date]).

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