Is TOE1 p.Gln258Pro (c.773A>C) pathogenic?

TOE1 p.Gln258Pro (c.773A>C) is classified Uncertain significance in TOE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-08-22). AlphaMissense: ambiguous (0.4396); Very rare (popmax 0.00401%, afr).

How common is TOE1 p.Gln258Pro (c.773A>C) in the general population?

TOE1 p.Gln258Pro (c.773A>C) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about TOE1 p.Gln258Pro (c.773A>C)?

AlphaMissense predicts ambiguous (score 0.4396) — an in-silico prediction, not a clinical call.

TOE1 p.Gln258Pro

c.773A>C · VCV4531048

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4396 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4396	ambiguous
REVEL	0.112	moderately benign-leaning
SaProt	LLR -12.54	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	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	17.52	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 0.00401% African / African-American · 3/74,900 alleles

Filtering AF 0.00215% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00191%

Overall 0.00235% 38/1,614,044 alleles · very rare exomes 35/1,461,882 · genomes 3/152,162 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,967
European (non-Finnish)	0.00297%	33,715

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.Gln258Pro
Coding: c.773A>C
MANE Select: NM_025077
Type: single nucleotide variant
Location: chr1:45342863 (GRCh38)
Gene constraint: LOEUF 1.225 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.16 · 1 PDB
Residue 258: a UniProt-annotated variant site (in pch7)

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

Similar variants

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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
TOE1 p.Arg184His 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-gln258pro (accessed [today's date]).

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