Is APP p.Glu437Asp (c.1311G>C) pathogenic?

APP p.Glu437Asp (c.1311G>C) is classified Uncertain significance in APP (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-26). AlphaMissense: likely benign (0.2715); Absent from gnomAD v4.1.

How common is APP p.Glu437Asp (c.1311G>C) in the general population?

APP p.Glu437Asp (c.1311G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about APP p.Glu437Asp (c.1311G>C)?

AlphaMissense predicts likely benign (score 0.2715) — an in-silico prediction, not a clinical call.

APP p.Glu437Asp

c.1311G>C · VCV4689716

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2715 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2715	likely benign
REVEL	0.223	benign-leaning
SaProt	LLR -6.64	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.33	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 0.059	GERP -1, phastCons 0.88
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

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: APP
Protein: p.Glu437Asp
Coding: c.1311G>C
MANE Select: NM_000484
Type: single nucleotide variant
Location: chr21:25975217 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 437: the e2 domain; an α-helix

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

Similar variants

APP p.Ala713Thr Likely pathogenic ★★ ⚠ same type
APP p.Asp694Asn Pathogenic ★★ ⚠ same type
APP p.Glu693Gln Pathogenic ★★ ⚠ same type
APP p.Ile716Phe Pathogenic ★★ ⚠ same type
APP p.Thr714Ala Pathogenic ★★ ⚠ same type
APP p.Val715Met Pathogenic/Likely pathogenic ★★ ⚠ same type
APP p.Val717Ile Pathogenic ★★ ⚠ same type
APP p.Val717Phe Pathogenic ★★ ⚠ same type

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-glu437asp (accessed [today's date]).

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