Is TOE1 p.Arg249Trp (c.745C>T) pathogenic?

TOE1 p.Arg249Trp (c.745C>T) is classified Conflicting classifications of pathogenicity in TOE1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-02-16). AlphaMissense: likely benign (0.3332); Very rare (popmax 0.00329%, sas); Associated with pontocerebellar hypoplasia type 7.

What condition is associated with TOE1 p.Arg249Trp (c.745C>T)?

TOE1 p.Arg249Trp (c.745C>T) is associated with pontocerebellar hypoplasia type 7 (ClinVar).

How common is TOE1 p.Arg249Trp (c.745C>T) in the general population?

TOE1 p.Arg249Trp (c.745C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about TOE1 p.Arg249Trp (c.745C>T)?

AlphaMissense predicts likely benign (score 0.3332) — an in-silico prediction, not a clinical call.

TOE1 p.Arg249Trp

c.745C>T · rs771979228 · VCV1036796

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.3332 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

pontocerebellar hypoplasia type 7

Computational evidence

Protein change
AlphaMissense	0.3332	likely benign
REVEL	0.312	indeterminate
SaProt	LLR -11.89	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP -0.28, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 3,446 bp · p 1.6e-05 · regional, not allelic
Overall
CADD	25.0	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 0.00329% South Asian · 3/91,060 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00062% 10/1,613,346 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,353
African / African-American	0.00267%	37,443
European (non-Finnish)	0.000424%	235,913

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.Arg249Trp
Coding: c.745C>T
MANE Select: NM_025077
dbSNP: rs771979228
Type: single nucleotide variant
Location: chr1:45342636 (GRCh38)
Gene constraint: LOEUF 1.225 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.16 · 1 PDB
Residue 249: a UniProt-annotated variant site (in pch7)

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

Disease context

pontocerebellar hypoplasia type 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TOE1 p.Arg249Gln Uncertain significance ★ ⚠ same residue
TOE1 p.Arg253Trp Uncertain significance ★★ ⚠ same condition
TOE1 p.Asp387Asn Uncertain significance ★★ ⚠ same condition
TOE1 p.Gln314Glu Uncertain significance ★★ ⚠ same condition
TOE1 p.Gly480Asp Uncertain significance ★★ ⚠ same condition
TOE1 p.Ile81Thr Uncertain significance ★★ ⚠ same condition
TOE1 c.237-2A>G Likely pathogenic ★ same condition
TOE1 c.913-2A>G Likely pathogenic ★ 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-arg249trp (accessed [today's date]).

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