Is BACE2 p.Asp216Glu (c.648C>G) pathogenic?

BACE2 p.Asp216Glu (c.648C>G) is classified Uncertain significance in BACE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-21). AlphaMissense: likely pathogenic (0.6614); Ultra-rare (popmax 0.033%, mid).

How common is BACE2 p.Asp216Glu (c.648C>G) in the general population?

BACE2 p.Asp216Glu (c.648C>G) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about BACE2 p.Asp216Glu (c.648C>G)?

AlphaMissense predicts likely pathogenic (score 0.6614) — an in-silico prediction, not a clinical call.

BACE2 p.Asp216Glu

c.648C>G · VCV3984175

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6614 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6614	likely pathogenic
REVEL	0.318	indeterminate
SaProt	LLR -7.63	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.86	GERP -4.2, phastCons 0.01
Regional constraint	o/e 0.82	unconstrained · MANE · 38 kb · p 0.00019 · regional, not allelic
Overall
CADD	19.54	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 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00171% 25/1,461,882 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
Admixed American	0.005%	20,008
European (non-Finnish)	0.00161%	62,106
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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: BACE2
Protein: p.Asp216Glu
Coding: c.648C>G
MANE Select: NM_012105
Type: single nucleotide variant
Location: chr21:41241848 (GRCh38)
Gene constraint: LOEUF 0.574 · pLI 0.73 (gnomAD)
Structure: AlphaFold pLDDT 83.31 · 19 PDB
Residue 216: an α-helix; the peptidase a1 domain

Full BACE2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BACE2 c.1135-10C>T Benign ★★ same type
BACE2 c.1304-8C>T Benign ★★ same type
BACE2 p.His56Tyr Benign ★★ ⚠ same type
BACE2 p.Ser88= Likely benign ★★ same type
BACE2 p.Ala200Gly Uncertain significance ★ ⚠ same type
BACE2 p.Ala25Val Uncertain significance ★ ⚠ same type
BACE2 p.Ala297Thr Uncertain significance ★ ⚠ same type
BACE2 p.Ala36Thr 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/bace2-p-asp216glu (accessed [today's date]).

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