Is BACE1 p.Val404Ile (c.1210G>A) pathogenic?

BACE1 p.Val404Ile (c.1210G>A) is classified Uncertain significance in BACE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-22). AlphaMissense: likely benign (0.2805); Ultra-rare (popmax 0.0121%, sas).

How common is BACE1 p.Val404Ile (c.1210G>A) in the general population?

BACE1 p.Val404Ile (c.1210G>A) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

What do computational predictors say about BACE1 p.Val404Ile (c.1210G>A)?

AlphaMissense predicts likely benign (score 0.2805) — an in-silico prediction, not a clinical call.

BACE1 p.Val404Ile

c.1210G>A · VCV4645029

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2805 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2805	likely benign
REVEL	0.549	indeterminate
SaProt	LLR -8.12	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 26 kb · p 2.5e-11 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.0121% South Asian · 11/91,088 alleles

Filtering AF 0.00676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.00254% 41/1,614,216 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,281
European (non-Finnish)	0.00246%	40,691
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: BACE1
Protein: p.Val404Ile
Coding: c.1210G>A
MANE Select: NM_012104
Type: single nucleotide variant
Location: chr11:117290542 (GRCh38)
Gene constraint: LOEUF 0.556 · pLI 0.76 (gnomAD)
Structure: AlphaFold pLDDT 87.75 · 431 PDB
Residue 404: a disulfide bond; the peptidase a1 domain; a β-strand

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-val404ile (accessed [today's date]).

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