Is TOE1 p.Phe148Tyr (c.443T>A) pathogenic?

TOE1 p.Phe148Tyr (c.443T>A) is classified Conflicting classifications of pathogenicity in TOE1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-08-26). AlphaMissense: likely pathogenic (0.829); Very rare (popmax 0.00297%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TOE1 p.Phe148Tyr (c.443T>A)?

TOE1 p.Phe148Tyr (c.443T>A) is associated with Inborn genetic diseases, pontocerebellar hypoplasia type 7 (ClinVar).

How common is TOE1 p.Phe148Tyr (c.443T>A) in the general population?

TOE1 p.Phe148Tyr (c.443T>A) is very rare (popmax 0.00297%, nfe) (gnomAD).

What do computational predictors say about TOE1 p.Phe148Tyr (c.443T>A)?

AlphaMissense predicts likely pathogenic (score 0.829) — an in-silico prediction, not a clinical call.

TOE1 p.Phe148Tyr

c.443T>A · rs148067486 · VCV417747

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.829 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00297%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.829	likely pathogenic
REVEL	0.508	indeterminate
SaProt	LLR -11.13	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	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	27.3	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 0.00297% European (non-Finnish) · 35/1,179,918 alleles

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

Overall 0.00223% 36/1,613,896 alleles · very rare exomes 30/1,461,710 · genomes 6/152,186 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00297%	33,712
Admixed American	0.00167%	59,996

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.Phe148Tyr
Coding: c.443T>A
MANE Select: NM_025077
dbSNP: rs148067486
Type: single nucleotide variant
Location: chr1:45342058 (GRCh38)
Gene constraint: LOEUF 1.225 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.16 · 1 PDB
Residue 148: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pontocerebellar hypoplasia type 7

Similar variants

TOE1 p.Arg184Cys Uncertain significance ★★ ⚠ same condition
TOE1 p.Arg184His Uncertain significance ★★ ⚠ same condition
TOE1 p.Arg185Gln Uncertain significance ★★ ⚠ same condition
TOE1 p.Arg253Trp Uncertain significance ★★ ⚠ same condition
TOE1 p.Arg293His Uncertain significance ★★ ⚠ same condition
TOE1 p.Arg494His Uncertain significance ★★ ⚠ same condition
TOE1 p.Asp387Asn Uncertain significance ★★ ⚠ same condition
TOE1 p.Gln314Glu Uncertain significance ★★ ⚠ 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-phe148tyr (accessed [today's date]).

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