Is BRCA1 p.Ala1453Glu (c.4358C>A) pathogenic?

BRCA1 p.Ala1453Glu (c.4358C>A) is classified Uncertain significance in BRCA1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-20). AlphaMissense: likely benign (0.1634); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA1 p.Ala1453Glu (c.4358C>A)?

BRCA1 p.Ala1453Glu (c.4358C>A) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA1 p.Ala1453Glu (c.4358C>A) in the general population?

BRCA1 p.Ala1453Glu (c.4358C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRCA1 p.Ala1453Glu (c.4358C>A)?

AlphaMissense predicts likely benign (score 0.1634) — an in-silico prediction, not a clinical call.

BRCA1 p.Ala1453Glu

c.4358C>A · rs1171055085 · VCV1479797

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1634 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,612,934)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1634	likely benign
REVEL	0.196	benign-leaning
SaProt	LLR -5.34	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.40	acceptor loss, 3 bp away · raw score · deltas
Pangolin	Δ0.22	gain · loss 0.15 · SpliceAI calls loss · independent
Constraint at this position
Conservation	phyloP 2.1	GERP -4.4, phastCons 0.99
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	15.41	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

No allele count reported in gnomAD v4.1 (AN 1,612,934). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: BRCA1
Protein: p.Ala1453Glu
Coding: c.4358C>A
MANE Select: NM_007294
dbSNP: rs1171055085
Type: single nucleotide variant
Location: chr17:43076614 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1453: the 'disordered' region; a UniProt-annotated variant site (in fancs)

Full BRCA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast ovarian cancer syndrome

Similar variants

BRCA1 p.Ala1453Ser Uncertain significance ★★ ⚠ same residue
BRCA1 p.Ala1453Thr Uncertain significance ★★ ⚠ same residue
BRCA1 p.Ala1453Val Uncertain significance ★★ ⚠ same residue
BRCA1 p.Ala1453= Conflicting classifications of pathogenicity ★ same residue
BRCA1 p.Ala1453Gly Uncertain significance ★ ⚠ same residue
BRCA1 c.134+3A>T Likely pathogenic ★★★ same condition
BRCA1 c.135-1G>T Pathogenic ★★★ same condition
BRCA1 c.212+1G>A Pathogenic ★★★ same condition

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/brca1-p-ala1453glu (accessed [today's date]).

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