Is APP p.Gly708= (c.2124C>T) pathogenic?

APP p.Gly708= (c.2124C>T) is classified Benign/Likely benign in APP (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-03-01). Rare (popmax 0.75%, afr); Associated with cerebral amyloid angiopathy, APP-related.

What condition is associated with APP p.Gly708= (c.2124C>T)?

APP p.Gly708= (c.2124C>T) is associated with cerebral amyloid angiopathy, APP-related, Alzheimer disease, Alzheimer disease type 1 (ClinVar).

How common is APP p.Gly708= (c.2124C>T) in the general population?

APP p.Gly708= (c.2124C>T) is rare (popmax 0.75%, afr) (gnomAD).

How is Hereditary cerebral amyloid angiopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

APP p.Gly708=

c.2124C>T · rs148888161 · VCV339629

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

gnomAD v4.1

Rare

rare (popmax 0.75%, afr)

Conditions

cerebral amyloid angiopathy, APP-related

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -3.7
Overall
CADD	7.92	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.75% African / African-American · 562/74,948 alleles

Filtering AF 0.699% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.678%

Overall 0.221% 3,562/1,613,822 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.75%	133
Remaining individualsnot grpmax-eligible	0.242%	414
European (non-Finnish)	0.216%	464
Admixed American	0.198%	504
East Asian	0.123%	816
Finnishnot grpmax-eligible	0.0985%	1,015
South Asian	0.0626%	1,597
Middle Eastern	0.0495%	2,020
Ashkenazi Jewishnot grpmax-eligible	0.027%	3,700

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.Gly708=
Coding: c.2124C>T
MANE Select: NM_000484
dbSNP: rs148888161
Type: single nucleotide variant
Location: chr21:25891809 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 708: a β-strand; the 'interaction with psen1' region

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

Disease context

cerebral amyloid angiopathy, APP-related — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Alzheimer disease Alzheimer disease type 1

For Hereditary cerebral amyloid angiopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

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
APP p.Val717Ile Pathogenic ★★ ⚠ same condition
APP p.Val717Phe 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-gly708 (accessed [today's date]).

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