Is TOE1 p.Arg259Gln (c.776G>A) pathogenic?

TOE1 p.Arg259Gln (c.776G>A) is classified Conflicting classifications of pathogenicity in TOE1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-11-11). AlphaMissense: likely benign (0.071); Rare (popmax 0.161%, sas); Associated with Inborn genetic diseases.

What condition is associated with TOE1 p.Arg259Gln (c.776G>A)?

TOE1 p.Arg259Gln (c.776G>A) is associated with Inborn genetic diseases (ClinVar).

How common is TOE1 p.Arg259Gln (c.776G>A) in the general population?

TOE1 p.Arg259Gln (c.776G>A) is rare (popmax 0.161%, sas) (gnomAD).

What do computational predictors say about TOE1 p.Arg259Gln (c.776G>A)?

AlphaMissense predicts likely benign (score 0.071) — an in-silico prediction, not a clinical call.

TOE1 p.Arg259Gln

c.776G>A · rs144829269 · VCV1408651

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.071 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.161%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.071	likely benign
REVEL	0.144	moderately benign-leaning
SaProt	LLR -7.03	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 -0.18	GERP 0.83, phastCons 0.041
Regional constraint	o/e 0.83	unconstrained · MANE · 3,446 bp · p 1.6e-05 · regional, not allelic
Overall
CADD	17.11	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 0.161% South Asian · 147/91,080 alleles

Filtering AF 0.14% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.132%

Overall 0.0184% 297/1,613,938 alleles · rare exomes 280/1,461,880 · genomes 17/152,058 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.161%	620
Admixed American	0.0167%	5,999
Middle Eastern	0.0164%	6,082
East Asian	0.0134%	7,479
European (non-Finnish)	0.0108%	9,291
Remaining individualsnot grpmax-eligible	0.0048%	20,829
African / African-American	0.00267%	37,433
Finnishnot grpmax-eligible	0.00156%	64,026

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.Arg259Gln
Coding: c.776G>A
MANE Select: NM_025077
dbSNP: rs144829269
Type: single nucleotide variant
Location: chr1:45342866 (GRCh38)
Gene constraint: LOEUF 1.225 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.16 · 1 PDB
Residue 259: 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.Arg259Trp 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-arg259gln (accessed [today's date]).

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