Is APP p.Glu246Lys (c.736G>A) pathogenic?

APP p.Glu246Lys (c.736G>A) is classified Conflicting classifications of pathogenicity in APP (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-07-20). AlphaMissense: likely benign (0.1301); Ultra-rare (popmax 0.0156%, eas); Associated with Alzheimer disease.

What condition is associated with APP p.Glu246Lys (c.736G>A)?

APP p.Glu246Lys (c.736G>A) is associated with Alzheimer disease (ClinVar).

How common is APP p.Glu246Lys (c.736G>A) in the general population?

APP p.Glu246Lys (c.736G>A) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about APP p.Glu246Lys (c.736G>A)?

AlphaMissense predicts likely benign (score 0.1301) — an in-silico prediction, not a clinical call.

APP p.Glu246Lys

c.736G>A · rs147485129 · VCV1695024

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1301 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Alzheimer disease

Computational evidence

Protein change
AlphaMissense	0.1301	likely benign
REVEL	0.267	benign-leaning
SaProt	LLR -10.07	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 1.3, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 289 kb · p 2e-07 · regional, not allelic
Overall
CADD	24.1	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 0.0156% East Asian · 7/44,886 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.00149% 24/1,613,790 alleles · ultra-rare exomes 21/1,461,634 · genomes 3/152,156 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,412
African / African-American	0.00534%	18,726
South Asian	0.0033%	30,337
European (non-Finnish)	0.000848%	117,993

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.Glu246Lys
Coding: c.736G>A
MANE Select: NM_000484
dbSNP: rs147485129
Type: single nucleotide variant
Location: chr21:26021969 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 246: the 'disordered' 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.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
APP p.Val717Phe 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-glu246lys (accessed [today's date]).

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