Is TOE1 p.Val20Leu (c.58G>C) pathogenic?

TOE1 p.Val20Leu (c.58G>C) is classified Benign in TOE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-02). AlphaMissense: likely benign (0.0804); Ultra-rare (popmax 0.0236%, nfe).

How common is TOE1 p.Val20Leu (c.58G>C) in the general population?

TOE1 p.Val20Leu (c.58G>C) is ultra-rare (popmax 0.0236%, nfe) (gnomAD).

What do computational predictors say about TOE1 p.Val20Leu (c.58G>C)?

AlphaMissense predicts likely benign (score 0.0804) — an in-silico prediction, not a clinical call.

TOE1 p.Val20Leu

c.58G>C · rs149814343 · VCV1599610

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0804 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0236%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0804	likely benign
REVEL	0.012	strongly benign-leaning
SaProt	LLR -7.07	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.32	GERP -0.18, phastCons 0.38
Regional constraint	o/e 0.83	unconstrained · MANE · 3,446 bp · p 1.6e-05 · regional, not allelic
Overall
CADD	19.4	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 0.0236% European (non-Finnish) · 279/1,180,032 alleles

Filtering AF 0.0213% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0205%

Overall 0.046% 743/1,614,228 alleles · ultra-rare exomes 665/1,461,882 · genomes 78/152,346 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.653%	153
Remaining individualsnot grpmax-eligible	0.064%	1,563
European (non-Finnish)grpmax	0.0236%	4,230
African / African-American	0.00533%	18,765
Admixed American	0.00333%	30,016

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.Val20Leu
Coding: c.58G>C
MANE Select: NM_025077
dbSNP: rs149814343
Type: single nucleotide variant
Location: chr1:45341078 (GRCh38)
Gene constraint: LOEUF 1.225 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.16 · 1 PDB
Residue 20: the 'disordered' region

Full TOE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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
TOE1 p.Arg184His 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-val20leu (accessed [today's date]).

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