Is TOE1 p.Arg339Gln (c.1016G>A) pathogenic?

TOE1 p.Arg339Gln (c.1016G>A) is classified Uncertain significance in TOE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-09-24). AlphaMissense: likely benign (0.117); Ultra-rare (popmax 0.0164%, mid).

How common is TOE1 p.Arg339Gln (c.1016G>A) in the general population?

TOE1 p.Arg339Gln (c.1016G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about TOE1 p.Arg339Gln (c.1016G>A)?

AlphaMissense predicts likely benign (score 0.117) — an in-silico prediction, not a clinical call.

TOE1 p.Arg339Gln

c.1016G>A · rs776880897 · VCV1312238

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.117 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.117	likely benign
REVEL	0.12	moderately benign-leaning
SaProt	LLR -6.42	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 9.9	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	23.9	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 · 1/6,084 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000682% 11/1,613,746 alleles · ultra-rare exomes 10/1,461,828 · genomes 1/151,918 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
East Asian	0.00223%	44,870
South Asian	0.0022%	45,530
Admixed American	0.00167%	59,980
African / African-American	0.00134%	74,788
European (non-Finnish)	0.000424%	236,003

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.Arg339Gln
Coding: c.1016G>A
MANE Select: NM_025077
dbSNP: rs776880897
Type: single nucleotide variant
Location: chr1:45343185 (GRCh38)
Gene constraint: LOEUF 1.225 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.16 · 1 PDB
Residue 339: a UniProt-annotated variant site (in pch7); the 'disordered' region

Full TOE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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MUTYH p.Pro3Leu Uncertain significance ★★ ⚠ same type
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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-arg339gln (accessed [today's date]).

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