Is BACE2 p.Val145Leu (c.433G>C) pathogenic?

BACE2 p.Val145Leu (c.433G>C) is classified Uncertain significance in BACE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-02). AlphaMissense: likely pathogenic (0.7936); Very rare (popmax 0.000763%, nfe).

How common is BACE2 p.Val145Leu (c.433G>C) in the general population?

BACE2 p.Val145Leu (c.433G>C) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about BACE2 p.Val145Leu (c.433G>C)?

AlphaMissense predicts likely pathogenic (score 0.7936) — an in-silico prediction, not a clinical call.

BACE2 p.Val145Leu

c.433G>C · rs369116567 · VCV2240226

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7936 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7936	likely pathogenic
REVEL	0.159	moderately benign-leaning
SaProt	LLR -7.53	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 69 kb · p 0.41 · regional, not allelic
Overall
CADD	23.2	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 0.000763% European (non-Finnish) · 9/1,180,014 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,613,998 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: BACE2
Protein: p.Val145Leu
Coding: c.433G>C
MANE Select: NM_012105
dbSNP: rs369116567
Type: single nucleotide variant
Location: chr21:41237544 (GRCh38)
Gene constraint: LOEUF 0.574 · pLI 0.73 (gnomAD)
Structure: AlphaFold pLDDT 83.31 · 19 PDB
Residue 145: a β-strand; the peptidase a1 domain

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

Similar variants

BACE2 p.Val145Ile Uncertain significance ★ ⚠ same residue
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

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-val145leu (accessed [today's date]).

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