Is TOE1 p.Ser276Thr (c.827G>C) pathogenic?

TOE1 p.Ser276Thr (c.827G>C) is classified Benign/Likely benign in TOE1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-17). AlphaMissense: likely benign (0.0696); Rare (popmax 0.223%, eas); Associated with Inborn genetic diseases.

What condition is associated with TOE1 p.Ser276Thr (c.827G>C)?

TOE1 p.Ser276Thr (c.827G>C) is associated with Inborn genetic diseases (ClinVar).

How common is TOE1 p.Ser276Thr (c.827G>C) in the general population?

TOE1 p.Ser276Thr (c.827G>C) is rare (popmax 0.223%, eas) (gnomAD).

What do computational predictors say about TOE1 p.Ser276Thr (c.827G>C)?

AlphaMissense predicts likely benign (score 0.0696) — an in-silico prediction, not a clinical call.

TOE1 p.Ser276Thr

c.827G>C · rs142271220 · VCV1601575

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0696 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0696	likely benign
REVEL	0.147	moderately benign-leaning
SaProt	LLR -7.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.31	acceptor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 5.8	GERP 0.8, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 3,446 bp · p 1.6e-05 · regional, not allelic
Overall
CADD	21.8	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 0.223% East Asian · 100/44,828 alleles

Filtering AF 0.188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.174%

Overall 0.0348% 562/1,613,854 alleles · rare exomes 501/1,461,890 · genomes 61/151,964 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.288%	348
East Asiangrpmax	0.223%	448
Remaining individualsnot grpmax-eligible	0.0416%	2,404
European (non-Finnish)	0.0206%	4,856
Middle Eastern	0.0165%	6,062
South Asian	0.00659%	15,178
African / African-American	0.00267%	37,451

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.Ser276Thr
Coding: c.827G>C
MANE Select: NM_025077
dbSNP: rs142271220
Type: single nucleotide variant
Location: chr1:45342917 (GRCh38)
Gene constraint: LOEUF 1.225 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.16 · 1 PDB
Residue 276: a UniProt-annotated variant site (in pch7)

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.Ser276Gly Uncertain significance ★ ⚠ same residue
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

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-ser276thr (accessed [today's date]).

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