Is TOE1 p.Arg185Trp (c.553C>T) pathogenic?

TOE1 p.Arg185Trp (c.553C>T) is classified Conflicting classifications of pathogenicity in TOE1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-19). AlphaMissense: likely benign (0.1815); Ultra-rare (popmax 0.0107%, afr); Associated with pontocerebellar hypoplasia type 7.

What condition is associated with TOE1 p.Arg185Trp (c.553C>T)?

TOE1 p.Arg185Trp (c.553C>T) is associated with pontocerebellar hypoplasia type 7 (ClinVar).

How common is TOE1 p.Arg185Trp (c.553C>T) in the general population?

TOE1 p.Arg185Trp (c.553C>T) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about TOE1 p.Arg185Trp (c.553C>T)?

AlphaMissense predicts likely benign (score 0.1815) — an in-silico prediction, not a clinical call.

TOE1 p.Arg185Trp

c.553C>T · rs767923015 · VCV1895807

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1815 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pontocerebellar hypoplasia type 7

Computational evidence

Protein change
AlphaMissense	0.1815	likely benign
REVEL	0.25	benign-leaning
SaProt	LLR -13.93	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.8, phastCons 0.99
Regional constraint	o/e 0.83	unconstrained · MANE · 3,446 bp · p 1.6e-05 · regional, not allelic
Overall
CADD	28.1	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 0.0107% African / African-American · 8/74,884 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00112% 18/1,614,032 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,360
South Asian	0.0022%	45,545
Admixed American	0.00167%	59,998
European (non-Finnish)	0.000593%	168,578

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.Arg185Trp
Coding: c.553C>T
MANE Select: NM_025077
dbSNP: rs767923015
Type: single nucleotide variant
Location: chr1:45342444 (GRCh38)
Gene constraint: LOEUF 1.225 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.16 · 1 PDB

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.Arg185Gln 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-arg185trp (accessed [today's date]).

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