Is APP p.Lys134Arg (c.401A>G) pathogenic?

APP p.Lys134Arg (c.401A>G) is classified Likely benign in APP (ClinVar, Single submitter, 2 submitters; last evaluated 2025-12-14). AlphaMissense: likely benign (0.0852); Ultra-rare (popmax 0.0107%, afr); Associated with Alzheimer disease.

What condition is associated with APP p.Lys134Arg (c.401A>G)?

APP p.Lys134Arg (c.401A>G) is associated with Alzheimer disease (ClinVar).

How common is APP p.Lys134Arg (c.401A>G) in the general population?

APP p.Lys134Arg (c.401A>G) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about APP p.Lys134Arg (c.401A>G)?

AlphaMissense predicts likely benign (score 0.0852) — an in-silico prediction, not a clinical call.

APP p.Lys134Arg

c.401A>G · VCV4453454

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0852 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Alzheimer disease

Computational evidence

Protein change
AlphaMissense	0.0852	likely benign
REVEL	0.616	indeterminate
SaProt	LLR -7.47	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.27	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 7.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 289 kb · p 2e-07 · regional, not allelic
Overall
CADD	26.0	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 0.0107% African / African-American · 8/74,996 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000806% 13/1,613,882 alleles · ultra-rare exomes 5/1,461,706 · genomes 8/152,176 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,375
Remaining individualsnot grpmax-eligible	0.0064%	15,625
Admixed American	0.00167%	60,012

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.Lys134Arg
Coding: c.401A>G
MANE Select: NM_000484
Type: single nucleotide variant
Location: chr21:26053303 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 134: the e1 domain; a β-strand; the 'cubd subdomain' 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.Lys134= 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-lys134arg (accessed [today's date]).

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