Is BACE1 p.Ala459Asp (c.1376C>A) pathogenic?

BACE1 p.Ala459Asp (c.1376C>A) is classified Uncertain significance in BACE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-05). AlphaMissense: likely pathogenic (0.9985); Absent from gnomAD v4.1.

How common is BACE1 p.Ala459Asp (c.1376C>A) in the general population?

BACE1 p.Ala459Asp (c.1376C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BACE1 p.Ala459Asp (c.1376C>A)?

AlphaMissense predicts likely pathogenic (score 0.9985) — an in-silico prediction, not a clinical call.

BACE1 p.Ala459Asp

c.1376C>A · rs2539869157 · VCV3132762

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9985 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9985	likely pathogenic · top 8% in BACE1
REVEL	0.665	pathogenic-leaning
SaProt	LLR -11.05	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 26 kb · p 2.5e-11 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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: BACE1
Protein: p.Ala459Asp
Coding: c.1376C>A
MANE Select: NM_012104
dbSNP: rs2539869157
Type: single nucleotide variant
Location: chr11:117289696 (GRCh38)
Gene constraint: LOEUF 0.556 · pLI 0.76 (gnomAD)
Structure: AlphaFold pLDDT 87.75 · 431 PDB

Full BACE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BACE1 p.Ala104Asp Uncertain significance ★ ⚠ same type
BACE1 p.Ala185Val Uncertain significance ★ ⚠ same type
BACE1 p.Ala304Pro Uncertain significance ★ ⚠ same type
BACE1 p.Ala312Val Uncertain significance ★ ⚠ same type
BACE1 p.Ala409Val Uncertain significance ★ ⚠ same type
BACE1 p.Arg122Gln Uncertain significance ★ ⚠ same type
BACE1 p.Arg255Gln Uncertain significance ★ ⚠ same type
BACE1 p.Arg255Trp Uncertain significance ★ 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/bace1-p-ala459asp (accessed [today's date]).

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