Is TOE1 p.Lys396Arg (c.1187A>G) pathogenic?

TOE1 p.Lys396Arg (c.1187A>G) is classified Uncertain significance in TOE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-22). AlphaMissense: likely benign (0.0638); Ultra-rare (popmax 0.052%, afr); Associated with Inborn genetic diseases.

What condition is associated with TOE1 p.Lys396Arg (c.1187A>G)?

TOE1 p.Lys396Arg (c.1187A>G) is associated with Inborn genetic diseases (ClinVar).

How common is TOE1 p.Lys396Arg (c.1187A>G) in the general population?

TOE1 p.Lys396Arg (c.1187A>G) is ultra-rare (popmax 0.052%, afr) (gnomAD).

What do computational predictors say about TOE1 p.Lys396Arg (c.1187A>G)?

AlphaMissense predicts likely benign (score 0.0638) — an in-silico prediction, not a clinical call.

TOE1 p.Lys396Arg

c.1187A>G · VCV4633392

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0638 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.052%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0638	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -6.51	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.36	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 2.9	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	8.322	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.052% African / African-American · 39/75,024 alleles

Filtering AF 0.039% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0345%

Overall 0.00502% 81/1,614,104 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.052%	1,924
Remaining individualsnot grpmax-eligible	0.008%	12,501
Admixed American	0.00666%	15,008
European (non-Finnish)	0.0028%	35,758

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.Lys396Arg
Coding: c.1187A>G
MANE Select: NM_025077
Type: single nucleotide variant
Location: chr1:45343356 (GRCh38)
Gene constraint: LOEUF 1.225 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.16 · 1 PDB
Residue 396: 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

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

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.Pro366Leu Uncertain significance ★★ ⚠ same condition
TOE1 p.Pro366Ser 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-lys396arg (accessed [today's date]).

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