Is BRCA1 p.Asp1840Ala (c.5519A>C) pathogenic?

BRCA1 p.Asp1840Ala (c.5519A>C) is classified Uncertain significance in BRCA1 (ClinVar, Single submitter, 2 submitters; last evaluated 2019-12-11). AlphaMissense: likely pathogenic (0.966); Absent from gnomAD v4.1; Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with BRCA1 p.Asp1840Ala (c.5519A>C)?

BRCA1 p.Asp1840Ala (c.5519A>C) is associated with hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA1 p.Asp1840Ala (c.5519A>C) in the general population?

BRCA1 p.Asp1840Ala (c.5519A>C) is absent from gnomAD v4.1 (gnomAD).

How is Hereditary breast and/or ovarian cancer syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about BRCA1 p.Asp1840Ala (c.5519A>C)?

AlphaMissense predicts likely pathogenic (score 0.966) — an in-silico prediction, not a clinical call.

BRCA1 p.Asp1840Ala

c.5519A>C · rs2050874260 · VCV861117

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.966 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.966	likely pathogenic · top 1% in BRCA1
REVEL	0.835	moderately pathogenic-leaning
SaProt	LLR -10.21	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BRCA1
Protein: p.Asp1840Ala
Coding: c.5519A>C
MANE Select: NM_007294
dbSNP: rs2050874260
Type: single nucleotide variant
Location: chr17:43045751 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1840: a UniProt-annotated variant site (in fancs); the brct 2 domain; an α-helix

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

Disease context

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

For Hereditary breast and/or ovarian cancer syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA1 p.Asp1840Tyr Uncertain significance ★★ ⚠ same residue
BRCA1 p.Asp1840Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Asp1840Glu Uncertain significance ★ ⚠ same residue
BRCA1 p.Asp1840= Likely benign ★ 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
BRCA1 c.212+1G>T 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-asp1840ala (accessed [today's date]).

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