Is BACE1 p.Ser166Ala (c.496T>G) pathogenic?

BACE1 p.Ser166Ala (c.496T>G) is classified Uncertain significance in BACE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-03). AlphaMissense: likely pathogenic (0.7057); Very rare (popmax 0.000593%, nfe).

How common is BACE1 p.Ser166Ala (c.496T>G) in the general population?

BACE1 p.Ser166Ala (c.496T>G) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about BACE1 p.Ser166Ala (c.496T>G)?

AlphaMissense predicts likely pathogenic (score 0.7057) — an in-silico prediction, not a clinical call.

BACE1 p.Ser166Ala

c.496T>G · VCV3474122

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7057 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7057	likely pathogenic
REVEL	0.39	indeterminate
SaProt	LLR -8.38	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 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 26 kb · p 2.5e-11 · regional, not allelic
Overall
CADD	25.7	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 0.000593% European (non-Finnish) · 7/1,180,020 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000479% 7/1,461,894 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: BACE1
Protein: p.Ser166Ala
Coding: c.496T>G
MANE Select: NM_012104
Type: single nucleotide variant
Location: chr11:117295202 (GRCh38)
Gene constraint: LOEUF 0.556 · pLI 0.76 (gnomAD)
Structure: AlphaFold pLDDT 87.75 · 431 PDB
Residue 166: a β-strand; the peptidase a1 domain

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.Ala459Asp Uncertain significance ★ ⚠ same type
BACE1 p.Arg122Gln Uncertain significance ★ ⚠ same type
BACE1 p.Arg255Gln 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-ser166ala (accessed [today's date]).

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