Is BRCA1 p.Asp1692Ala (c.5075A>C) pathogenic?

BRCA1 p.Asp1692Ala (c.5075A>C) is classified Conflicting classifications of pathogenicity in BRCA1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-04-23). AlphaMissense: likely pathogenic (0.7891); Absent from gnomAD v4.1; Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with BRCA1 p.Asp1692Ala (c.5075A>C)?

BRCA1 p.Asp1692Ala (c.5075A>C) is associated with hereditary breast ovarian cancer syndrome, breast cancer, breast-ovarian cancer, familial, susceptibility to, 1 (ClinVar).

How common is BRCA1 p.Asp1692Ala (c.5075A>C) in the general population?

BRCA1 p.Asp1692Ala (c.5075A>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.Asp1692Ala (c.5075A>C)?

AlphaMissense predicts likely pathogenic (score 0.7891) — an in-silico prediction, not a clinical call.

BRCA1 p.Asp1692Ala

c.5075A>C · rs397509222 · VCV254641

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.7891 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.7891	likely pathogenic · top 5% in BRCA1
REVEL	0.784	moderately pathogenic-leaning
SaProt	LLR -8.69	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	Δ0.20	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 7.8	GERP 2.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	24.6	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

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.Asp1692Ala
Coding: c.5075A>C
MANE Select: NM_007294
dbSNP: rs397509222
Type: single nucleotide variant
Location: chr17:43063951 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1692: the brct 1 domain; a UniProt-annotated variant site (in fancs); a UniProt-annotated variant site (in ovarian cancer; uncertain significance)

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

Also linked: breast cancer breast-ovarian cancer, familial, susceptibility to, 1

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA1 p.Asp1692Asn Pathogenic ★★★ ⚠ same residue
BRCA1 p.Asp1692His Pathogenic ★★★ same residue
BRCA1 p.Asp1692Val Likely pathogenic ★★★ same residue
BRCA1 p.Asp1692Tyr Pathogenic ★ same residue
BRCA1 p.Asp1692Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Asp1692fs Pathogenic ★★★ same residue
BRCA1 p.Asp1692_Trp1718delinsGly Pathogenic ★ same residue
BRCA1 c.134+3A>T Likely 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-asp1692ala (accessed [today's date]).

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