Is APP p.Thr280del (c.819CAC[6]) pathogenic?

APP p.Thr280del (c.819CAC[6]) is classified Uncertain significance in APP (ClinVar, Single submitter, 2 submitters; last evaluated 2023-03-13). Very rare (popmax 0.00536%, afr).

How common is APP p.Thr280del (c.819CAC[6]) in the general population?

APP p.Thr280del (c.819CAC[6]) is very rare (popmax 0.00536%, afr) (gnomAD).

APP p.Thr280del

c.819CAC[6] · rs527890624 · VCV2684335

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00536%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -20	GERP -2.7
Overall
CADD	18.73	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	(GTG)n simple repeat · ambiguous alignment · confidence, not pathogenicity

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00536% African / African-American · 4/74,684 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00354% 57/1,609,226 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0394%	2,537
African / African-Americangrpmax	0.00536%	18,671
Remaining individualsnot grpmax-eligible	0.00321%	31,140
South Asian	0.00221%	45,302
European (non-Finnish)	0.00204%	49,052

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: APP
Protein: p.Thr280del
Coding: c.819CAC[6]
MANE Select: NM_000484
dbSNP: rs527890624
Type: Microsatellite
Location: chr21:26021866 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 280: the 'disordered' region

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

Similar variants

APP p.Thr280dup Conflicting classifications of pathogenicity ★ same residue
APP p.Glu241_Ala242insGlu Uncertain significance ★ same type
APP p.Glu241del Uncertain significance ★ same type
APP p.Glu665del Uncertain significance ★ same type
APP p.Thr278_Thr280del Uncertain significance ★ same type
APP p.Thr279_Thr280del Uncertain significance ★ same type
APP p.Thr279_Thr280dup Uncertain significance ★ same type
APP c.1091-20_1091-18del Likely benign ★ 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/app-p-thr280del (accessed [today's date]).

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