Is APP p.Gly322= (c.966C>T) pathogenic?

APP p.Gly322= (c.966C>T) is classified Likely benign in APP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-10). Ultra-rare (popmax 0.0165%, mid); Associated with Alzheimer disease.

What condition is associated with APP p.Gly322= (c.966C>T)?

APP p.Gly322= (c.966C>T) is associated with Alzheimer disease (ClinVar).

How common is APP p.Gly322= (c.966C>T) in the general population?

APP p.Gly322= (c.966C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

APP p.Gly322=

c.966C>T · VCV3616417

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

Alzheimer disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.25	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 0.24, phastCons 1
Overall
CADD	14.93	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.00229% 37/1,614,126 alleles · ultra-rare exomes 33/1,461,840 · genomes 4/152,286 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
East Asian	0.0156%	6,411
Remaining individualsnot grpmax-eligible	0.0048%	20,835
Admixed American	0.00333%	30,009
African / African-American	0.00267%	37,512
European (non-Finnish)	0.00186%	53,637

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.Gly322=
Coding: c.966C>T
MANE Select: NM_000484
Type: single nucleotide variant
Location: chr21:26000082 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 322: the bpti/kunitz inhibitor domain

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.Gly322Ser Likely benign ★ 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
APP p.Val717Ile 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-gly322 (accessed [today's date]).

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