Is APP p.Ala713= (c.2139G>A) pathogenic?

APP p.Ala713= (c.2139G>A) is classified Likely benign in APP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-16). Very rare (popmax 0.004%, afr); Associated with Alzheimer disease.

What condition is associated with APP p.Ala713= (c.2139G>A)?

APP p.Ala713= (c.2139G>A) is associated with Alzheimer disease (ClinVar).

How common is APP p.Ala713= (c.2139G>A) in the general population?

APP p.Ala713= (c.2139G>A) is very rare (popmax 0.004%, afr) (gnomAD).

APP p.Ala713=

c.2139G>A · rs749919142 · VCV1623260

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Conditions

Alzheimer disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.084	GERP -3.8, phastCons 0.98
Overall
CADD	10.81	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/75,030 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000494%

Overall 0.00062% 10/1,614,086 alleles · very rare exomes 10/1,461,818 · genomes 0/152,268 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	25,010
East Asian	0.00223%	44,886
Remaining individualsnot grpmax-eligible	0.0016%	62,502
South Asian	0.0011%	91,074
European (non-Finnish)	0.000339%	294,993

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.Ala713=
Coding: c.2139G>A
MANE Select: NM_000484
dbSNP: rs749919142
Type: single nucleotide variant
Location: chr21:25891794 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 713: a UniProt-annotated variant site (in ad1); a UniProt-annotated variant site (in one chronic schizophrenia patient; uncertain significance); an α-helix; the 'interaction with psen1' region; a functional site (cleavage; by gamma-secretase; site 2)

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.Ala713Thr Likely pathogenic ★★ ⚠ same residue
APP p.Ala713Glu Likely pathogenic ★ same residue
APP p.Ala713Val Conflicting classifications of pathogenicity ★ ⚠ same residue
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-ala713 (accessed [today's date]).

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