Is BACE1 p.Pro85Leu (c.254C>T) pathogenic?

BACE1 p.Pro85Leu (c.254C>T) is classified Uncertain significance in BACE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-19). AlphaMissense: ambiguous (0.3598); Ultra-rare (popmax 0.0102%, nfe).

How common is BACE1 p.Pro85Leu (c.254C>T) in the general population?

BACE1 p.Pro85Leu (c.254C>T) is ultra-rare (popmax 0.0102%, nfe) (gnomAD).

What do computational predictors say about BACE1 p.Pro85Leu (c.254C>T)?

AlphaMissense predicts ambiguous (score 0.3598) — an in-silico prediction, not a clinical call.

BACE1 p.Pro85Leu

c.254C>T · rs759924602 · VCV2525596

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3598 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0102%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3598	ambiguous
REVEL	0.406	indeterminate
SaProt	LLR -11.98	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 26 kb · p 2.5e-11 · regional, not allelic
Overall
CADD	28.4	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 0.0102% European (non-Finnish) · 119/1,166,606 alleles

Filtering AF 0.00869% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00813%

Overall 0.00809% 128/1,582,278 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0102%	9,803
Remaining individualsnot grpmax-eligible	0.0098%	10,203
African / African-American	0.0042%	23,805

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.Pro85Leu
Coding: c.254C>T
MANE Select: NM_012104
dbSNP: rs759924602
Type: single nucleotide variant
Location: chr11:117315542 (GRCh38)
Gene constraint: LOEUF 0.556 · pLI 0.76 (gnomAD)
Structure: AlphaFold pLDDT 87.75 · 431 PDB
Residue 85: a turn; 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-pro85leu (accessed [today's date]).

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