Is TOE1 p.Arg494His (c.1481G>A) pathogenic?

TOE1 p.Arg494His (c.1481G>A) is classified Uncertain significance in TOE1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-07). AlphaMissense: likely benign (0.0927); Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with TOE1 p.Arg494His (c.1481G>A)?

TOE1 p.Arg494His (c.1481G>A) is associated with Inborn genetic diseases (ClinVar).

How common is TOE1 p.Arg494His (c.1481G>A) in the general population?

TOE1 p.Arg494His (c.1481G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about TOE1 p.Arg494His (c.1481G>A)?

AlphaMissense predicts likely benign (score 0.0927) — an in-silico prediction, not a clinical call.

TOE1 p.Arg494His

c.1481G>A · rs745910227 · VCV1510871

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0927 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0927	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -6.87	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 3.4	GERP -1, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 3,446 bp · p 1.6e-05 · regional, not allelic
Overall
CADD	21.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00211% 34/1,613,418 alleles · ultra-rare exomes 29/1,461,338 · genomes 5/152,080 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
Remaining individualsnot grpmax-eligible	0.00961%	10,411
East Asian	0.00446%	22,437
South Asian	0.00439%	22,768
African / African-American	0.00401%	24,953
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
Admixed American	0.00333%	29,992
European (non-Finnish)	0.00127%	78,637

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.Arg494His
Coding: c.1481G>A
MANE Select: NM_025077
dbSNP: rs745910227
Type: single nucleotide variant
Location: chr1:45343650 (GRCh38)
Gene constraint: LOEUF 1.225 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.16 · 1 PDB
Residue 494: a UniProt-annotated variant site (in pch7); the 'disordered' region

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.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.Pro366Leu Uncertain significance ★★ ⚠ same condition
TOE1 p.Pro366Ser Uncertain significance ★★ ⚠ same condition
TOE1 p.Thr124Ile 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-arg494his (accessed [today's date]).

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