Is TOE1 p.Ser26Ala (c.76T>G) pathogenic?

TOE1 p.Ser26Ala (c.76T>G) is classified Benign in TOE1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.0582); Common (popmax 13.3%, amr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about TOE1 p.Ser26Ala (c.76T>G)?

AlphaMissense predicts likely benign (score 0.0582) — an in-silico prediction, not a clinical call.

TOE1 p.Ser26Ala

Q: How common is TOE1 p.Ser26Ala (c.76T>G) in the general population?

TOE1 p.Ser26Ala (c.76T>G) is common (popmax 13.3%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.76T>G · rs148620104 · VCV1275525

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0582 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 13.3%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0582	likely benign
REVEL	0.015	strongly benign-leaning
SaProt	LLR -5.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.11	GERP -0.52, phastCons 0.27
Regional constraint	o/e 0.83	unconstrained · MANE · 3,446 bp · p 1.6e-05 · regional, not allelic
Overall
CADD	16.79	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 13.3% Admixed American · 7,977/60,012 alleles

Filtering AF 13% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.9%

Overall 0.538% 8,679/1,614,128 alleles · common exomes 7,189/1,461,888 · genomes 1,490/152,240 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	13.3%	8
Remaining individualsnot grpmax-eligible	0.461%	217
Middle Eastern	0.165%	606
African / African-American	0.124%	807
South Asian	0.103%	969
Ashkenazi Jewishnot grpmax-eligible	0.027%	3,701
European (non-Finnish)	0.0174%	5,756
East Asian	0.00891%	11,222

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.Ser26Ala
Coding: c.76T>G
MANE Select: NM_025077
dbSNP: rs148620104
Type: single nucleotide variant
Location: chr1:45341096 (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.Ser26Cys Uncertain significance ★ ⚠ 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-ser26ala (accessed [today's date]).

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