Is TOE1 p.Ser496Phe (c.1487C>T) pathogenic?

TOE1 p.Ser496Phe (c.1487C>T) is classified Likely pathogenic in TOE1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2017-07-16). AlphaMissense: likely pathogenic (0.9652); Very rare (popmax 0.000509%, nfe); Associated with pontocerebellar hypoplasia type 7.

What condition is associated with TOE1 p.Ser496Phe (c.1487C>T)?

TOE1 p.Ser496Phe (c.1487C>T) is associated with pontocerebellar hypoplasia type 7 (ClinVar).

How common is TOE1 p.Ser496Phe (c.1487C>T) in the general population?

TOE1 p.Ser496Phe (c.1487C>T) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about TOE1 p.Ser496Phe (c.1487C>T)?

AlphaMissense predicts likely pathogenic (score 0.9652) — an in-silico prediction, not a clinical call.

TOE1 p.Ser496Phe

c.1487C>T · rs1570626350 · VCV690340

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9652 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

pontocerebellar hypoplasia type 7

Computational evidence

Protein change
AlphaMissense	0.9652	likely pathogenic ✓ concordant with ClinVar · top 10% in TOE1
REVEL	0.341	indeterminate
SaProt	LLR -15.20	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 7.7	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	26.9	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 0.000509% European (non-Finnish) · 6/1,178,614 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,612,462 alleles · very rare exomes 6/1,460,242 · genomes 0/152,220 · joint denominator

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.Ser496Phe
Coding: c.1487C>T
MANE Select: NM_025077
dbSNP: rs1570626350
Type: single nucleotide variant
Location: chr1:45343656 (GRCh38)
Gene constraint: LOEUF 1.225 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.16 · 1 PDB
Residue 496: a UniProt-annotated variant site (in pch7); the 'disordered' region

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-ser496phe (accessed [today's date]).

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