Is TOE1 p.Pro35Leu (c.104C>T) pathogenic?

TOE1 p.Pro35Leu (c.104C>T) is classified Conflicting classifications of pathogenicity in TOE1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-09-12). AlphaMissense: likely pathogenic (0.6865); Very rare (popmax 0.00373%, nfe).

How common is TOE1 p.Pro35Leu (c.104C>T) in the general population?

TOE1 p.Pro35Leu (c.104C>T) is very rare (popmax 0.00373%, nfe) (gnomAD).

What do computational predictors say about TOE1 p.Pro35Leu (c.104C>T)?

AlphaMissense predicts likely pathogenic (score 0.6865) — an in-silico prediction, not a clinical call.

TOE1 p.Pro35Leu

c.104C>T · rs754389983 · VCV766496

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6865 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00373%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6865	likely pathogenic
REVEL	0.504	indeterminate
SaProt	LLR -11.71	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 1.8, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 3,446 bp · p 1.6e-05 · regional, not allelic
Overall
CADD	27.8	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 0.00373% European (non-Finnish) · 44/1,180,046 alleles

Filtering AF 0.00283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.011% 177/1,614,068 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.203%	493
European (non-Finnish)grpmax	0.00373%	26,819
Remaining individualsnot grpmax-eligible	0.0032%	31,245
South Asian	0.0011%	91,084

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro35Leu
Coding: c.104C>T
MANE Select: NM_025077
dbSNP: rs754389983
Type: single nucleotide variant
Location: chr1:45341124 (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

Similar variants

TOE1 p.Pro35= Likely benign ★ same residue
MUTYH p.Trp12Ter Pathogenic/Likely pathogenic ★★ same type
TOE1 p.Glu245Ter Pathogenic ★★ same type
MUTYH c.36+5G>A Uncertain significance ★★ same type
MUTYH p.Arg10His Uncertain significance ★★ ⚠ same type
MUTYH p.Arg7Leu Uncertain significance ★★ ⚠ same type
MUTYH p.Pro3Leu Uncertain significance ★★ ⚠ same type
TOE1 p.Arg184Cys Uncertain significance ★★ ⚠ same type

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-pro35leu (accessed [today's date]).

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