Is TOE1 p.Arg439Trp (c.1315C>T) pathogenic?

TOE1 p.Arg439Trp (c.1315C>T) is classified Uncertain significance in TOE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-22). AlphaMissense: likely pathogenic (0.6616); Ultra-rare (popmax 0.0164%, mid).

How common is TOE1 p.Arg439Trp (c.1315C>T) in the general population?

TOE1 p.Arg439Trp (c.1315C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about TOE1 p.Arg439Trp (c.1315C>T)?

AlphaMissense predicts likely pathogenic (score 0.6616) — an in-silico prediction, not a clinical call.

TOE1 p.Arg439Trp

c.1315C>T · rs377031691 · VCV1906868

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6616 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6616	likely pathogenic
REVEL	0.419	indeterminate
SaProt	LLR -11.79	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 3,446 bp · p 1.6e-05 · regional, not allelic
Overall
CADD	28.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00911% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00855%

Overall 0.00905% 146/1,613,986 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0236%	4,229
Middle Easterngrpmax	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0144%	6,943
European (non-Finnish)	0.0107%	9,365
Admixed American	0.00333%	29,999
South Asian	0.0011%	91,078

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg439Trp
Coding: c.1315C>T
MANE Select: NM_025077
dbSNP: rs377031691
Type: single nucleotide variant
Location: chr1:45343484 (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

Similar variants

TOE1 p.Arg439Gln Uncertain significance ★ same residue
MUTYH p.Trp12Ter Pathogenic/Likely pathogenic ★★ same type
TOE1 p.Glu245Ter Pathogenic ★★ same type
MUTYH c.36+5G>A Uncertain significance ★★ same type
MUTYH p.Arg10His Uncertain significance ★★ ⚠ same type
MUTYH p.Arg7Leu Uncertain significance ★★ ⚠ same type
MUTYH p.Pro3Leu Uncertain significance ★★ ⚠ same type
TOE1 p.Arg184Cys Uncertain significance ★★ ⚠ same type

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-arg439trp (accessed [today's date]).

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