Is APP p.Ala416= (c.1248A>G) pathogenic?

APP p.Ala416= (c.1248A>G) is classified Likely benign in APP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-19). Ultra-rare (popmax 0.0306%, afr); Associated with Alzheimer disease.

What condition is associated with APP p.Ala416= (c.1248A>G)?

APP p.Ala416= (c.1248A>G) is associated with Alzheimer disease (ClinVar).

How common is APP p.Ala416= (c.1248A>G) in the general population?

APP p.Ala416= (c.1248A>G) is ultra-rare (popmax 0.0306%, afr) (gnomAD).

APP p.Ala416=

c.1248A>G · rs556540232 · VCV717600

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0306%, afr)

Conditions

Alzheimer disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.012	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.4	GERP -3.9
Overall
CADD	9.141	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0306% African / African-American · 23/75,054 alleles

Filtering AF 0.0209% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0177%

Overall 0.00143% 23/1,613,918 alleles · ultra-rare exomes 10/1,461,554 · genomes 13/152,364 · joint denominator

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.Ala416=
Coding: c.1248A>G
MANE Select: NM_000484
dbSNP: rs556540232
Type: single nucleotide variant
Location: chr21:25976005 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 416: an α-helix; the e2 domain; the 'heparin-binding' 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.Ala416Val 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
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-ala416 (accessed [today's date]).

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