Is APP p.Met43Val (c.127A>G) pathogenic?

APP p.Met43Val (c.127A>G) is classified Uncertain significance in APP (ClinVar, No assertion criteria, 1 submitter; last evaluated 2026-04-20). AlphaMissense: ambiguous (0.4251); Very rare (popmax 8.47e-05%, nfe); Associated with Alzheimer disease type 1.

What condition is associated with APP p.Met43Val (c.127A>G)?

APP p.Met43Val (c.127A>G) is associated with Alzheimer disease type 1 (ClinVar).

How common is APP p.Met43Val (c.127A>G) in the general population?

APP p.Met43Val (c.127A>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about APP p.Met43Val (c.127A>G)?

AlphaMissense predicts ambiguous (score 0.4251) — an in-silico prediction, not a clinical call.

APP p.Met43Val

Q: How is Early-onset autosomal dominant Alzheimer disease inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.127A>G · VCV4849946

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4251 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Alzheimer disease type 1

Computational evidence

Protein change
AlphaMissense	0.4251	ambiguous
REVEL	0.893	moderately pathogenic-leaning
SaProt	LLR -13.27	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 289 kb · p 2e-07 · regional, not allelic
Overall
CADD	24.8	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 8.47e-05% European (non-Finnish) · 1/1,180,000 alleles

Overall 6.84e-05% 1/1,461,860 alleles · very rare

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.Met43Val
Coding: c.127A>G
MANE Select: NM_000484
Type: single nucleotide variant
Location: chr21:26112077 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 43: a β-strand; the e1 domain; the 'gfld subdomain' region; a disulfide bond

Full APP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Alzheimer disease type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Early-onset autosomal dominant Alzheimer disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

APP p.Ala713Thr Likely 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
APP p.Arg16Gln Uncertain significance ★★ ⚠ same condition
APP p.Glu665Asp Uncertain significance ★★ ⚠ same condition
APP p.Met338Val Uncertain significance ★★ ⚠ 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-met43val (accessed [today's date]).

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