Is TOE1 p.Arg439Gln (c.1316G>A) pathogenic?

TOE1 p.Arg439Gln (c.1316G>A) is classified Uncertain significance in TOE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-15). AlphaMissense: ambiguous (0.3485); Very rare (popmax 0.00153%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TOE1 p.Arg439Gln (c.1316G>A)?

TOE1 p.Arg439Gln (c.1316G>A) is associated with Inborn genetic diseases (ClinVar).

How common is TOE1 p.Arg439Gln (c.1316G>A) in the general population?

TOE1 p.Arg439Gln (c.1316G>A) is very rare (popmax 0.00153%, nfe) (gnomAD).

What do computational predictors say about TOE1 p.Arg439Gln (c.1316G>A)?

AlphaMissense predicts ambiguous (score 0.3485) — an in-silico prediction, not a clinical call.

TOE1 p.Arg439Gln

c.1316G>A · VCV4830183

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3485 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3485	ambiguous
REVEL	0.454	indeterminate
SaProt	LLR -5.69	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 0.99, 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 0.00153% European (non-Finnish) · 18/1,180,038 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00112% 18/1,614,168 alleles · very rare exomes 18/1,461,888 · genomes 0/152,280 · 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.Arg439Gln
Coding: c.1316G>A
MANE Select: NM_025077
Type: single nucleotide variant
Location: chr1:45343485 (GRCh38)
Gene constraint: LOEUF 1.225 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.16 · 1 PDB
Residue 439: 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.Arg439Trp Uncertain significance ★ ⚠ 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-arg439gln (accessed [today's date]).

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