Is TOE1 p.Glu220Lys (c.658G>A) pathogenic?

TOE1 p.Glu220Lys (c.658G>A) is classified Pathogenic/Likely pathogenic in TOE1 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2017-07-16). AlphaMissense: likely benign (0.2939); Absent from gnomAD v4.1; Associated with pontocerebellar hypoplasia type 7.

What condition is associated with TOE1 p.Glu220Lys (c.658G>A)?

TOE1 p.Glu220Lys (c.658G>A) is associated with pontocerebellar hypoplasia type 7 (ClinVar).

How common is TOE1 p.Glu220Lys (c.658G>A) in the general population?

TOE1 p.Glu220Lys (c.658G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TOE1 p.Glu220Lys (c.658G>A)?

AlphaMissense predicts likely benign (score 0.2939) — an in-silico prediction, not a clinical call.

TOE1 p.Glu220Lys

c.658G>A · rs1570621473 · VCV417746

Pathogenic/Likely pathogenic No assertion criteria

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2939 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pontocerebellar hypoplasia type 7

Computational evidence

Protein change
AlphaMissense	0.2939	likely benign ⚠ discordant with ClinVar
REVEL	0.265	benign-leaning
SaProt	LLR -11.69	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	Δ0.21	donor gain · deltas
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	33.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TOE1
Protein: p.Glu220Lys
Coding: c.658G>A
MANE Select: NM_025077
dbSNP: rs1570621473
Type: single nucleotide variant
Location: chr1:45342549 (GRCh38)
Gene constraint: LOEUF 1.225 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.16 · 1 PDB
Residue 220: a UniProt-annotated variant site (in pch7; reduced protein levels; decreased function in snrna 3'-end processing)

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.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
TOE1 p.Arg182Ter 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-glu220lys (accessed [today's date]).

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