Is APP p.Thr276Ser (c.826A>T) pathogenic?

APP p.Thr276Ser (c.826A>T) is classified Benign in APP (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-23). AlphaMissense: ambiguous (0.3543); Rare (popmax 0.536%, afr); Associated with Alzheimer disease.

What condition is associated with APP p.Thr276Ser (c.826A>T)?

APP p.Thr276Ser (c.826A>T) is associated with Alzheimer disease (ClinVar).

How common is APP p.Thr276Ser (c.826A>T) in the general population?

APP p.Thr276Ser (c.826A>T) is rare (popmax 0.536%, afr) (gnomAD).

What do computational predictors say about APP p.Thr276Ser (c.826A>T)?

AlphaMissense predicts ambiguous (score 0.3543) — an in-silico prediction, not a clinical call.

APP p.Thr276Ser

c.826A>T · rs202198008 · VCV704999

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.3543 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.536%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Alzheimer disease

Computational evidence

Protein change
AlphaMissense	0.3543	ambiguous
REVEL	0.283	benign-leaning
SaProt	LLR -9.23	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 1.4, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 289 kb · p 2e-07 · regional, not allelic
Overall
CADD	24.0	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 0.536% African / African-American · 402/74,968 alleles

Filtering AF 0.493% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.476%

Overall 0.029% 468/1,613,758 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.536%	186
Remaining individualsnot grpmax-eligible	0.048%	2,083
Admixed American	0.0467%	2,142
South Asian	0.0011%	91,042
European (non-Finnish)	0.000593%	168,563

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: APP
Protein: p.Thr276Ser
Coding: c.826A>T
MANE Select: NM_000484
dbSNP: rs202198008
Type: single nucleotide variant
Location: chr21:26021879 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 276: the 'disordered' region

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

Disease context

Alzheimer disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

APP p.Thr276= Likely benign ★ same residue
APP p.Thr276Ala Uncertain significance ★ ⚠ same residue
APP p.Ala713Thr Likely pathogenic ★★ ⚠ same condition
APP p.Asp694Asn Pathogenic ★★ ⚠ same condition
APP p.Glu693Gln Pathogenic ★★ ⚠ same condition
APP p.Ile716Phe Pathogenic ★★ ⚠ same condition
APP p.Thr714Ala Pathogenic ★★ ⚠ same condition
APP p.Val715Met Pathogenic/Likely pathogenic ★★ ⚠ 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/app-p-thr276ser (accessed [today's date]).

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