Is APP p.Ala713Val (c.2138C>T) pathogenic?

APP p.Ala713Val (c.2138C>T) is classified Conflicting classifications of pathogenicity in APP (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-09). AlphaMissense: likely pathogenic (0.823); Very rare (popmax 0.00636%, nfe); Associated with Alzheimer disease.

What condition is associated with APP p.Ala713Val (c.2138C>T)?

APP p.Ala713Val (c.2138C>T) is associated with Alzheimer disease (ClinVar).

How common is APP p.Ala713Val (c.2138C>T) in the general population?

APP p.Ala713Val (c.2138C>T) is very rare (popmax 0.00636%, nfe) (gnomAD).

What do computational predictors say about APP p.Ala713Val (c.2138C>T)?

AlphaMissense predicts likely pathogenic (score 0.823) — an in-silico prediction, not a clinical call.

APP p.Ala713Val

c.2138C>T · rs1800557 · VCV98237

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.823 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00636%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Alzheimer disease

Computational evidence

Protein change
AlphaMissense	0.823	likely pathogenic
REVEL	0.928	moderately pathogenic-leaning
SaProt	LLR -5.81	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 289 kb · p 2e-07 · regional, not allelic
Overall
CADD	29.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00636% European (non-Finnish) · 75/1,179,914 alleles

Filtering AF 0.00519% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00474%

Overall 0.00527% 85/1,613,762 alleles · very rare exomes 79/1,461,776 · genomes 6/151,986 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.008%	12,496
European (non-Finnish)grpmax	0.00636%	15,732
Finnishnot grpmax-eligible	0.00313%	31,988
East Asian	0.00223%	44,882
Admixed American	0.00167%	59,976
African / African-American	0.00134%	74,872

Remaining individuals 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.Ala713Val
Coding: c.2138C>T
MANE Select: NM_000484
dbSNP: rs1800557
Type: single nucleotide variant
Location: chr21:25891795 (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.Ala713= Likely benign ★★ same residue
APP p.Ala713Glu Likely pathogenic ★ 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-ala713val (accessed [today's date]).

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