Is BRCA1 p.Glu188Val (c.563A>T) pathogenic?

BRCA1 p.Glu188Val (c.563A>T) is classified Uncertain significance in BRCA1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-11). AlphaMissense: ambiguous (0.4945); Absent from gnomAD v4.1; Associated with breast-ovarian cancer, familial, susceptibility to, 1.

How common is BRCA1 p.Glu188Val (c.563A>T) in the general population?

BRCA1 p.Glu188Val (c.563A>T) 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.Glu188Val (c.563A>T)?

AlphaMissense predicts ambiguous (score 0.4945) — an in-silico prediction, not a clinical call.

BRCA1 p.Glu188Val

Q: What condition is associated with BRCA1 p.Glu188Val (c.563A>T)?

BRCA1 p.Glu188Val (c.563A>T) is associated with breast-ovarian cancer, familial, susceptibility to, 1, hereditary neoplastic syndrome (ClinVar).

c.563A>T · VCV3340072

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4945 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

breast-ovarian cancer, familial, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.4945	ambiguous · top 9% in BRCA1
REVEL	0.716	pathogenic-leaning
SaProt	LLR -7.81	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.54	acceptor loss, 15 bp away · raw score · deltas
Pangolin	Δ0.65	loss · gain 0.02 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	25.7	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.Glu188Val
Coding: c.563A>T
MANE Select: NM_007294
Type: single nucleotide variant
Location: chr17:43097274 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB

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

Disease context

breast-ovarian cancer, familial, susceptibility to, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA1 p.Glu188= Likely benign ★★★ same residue
BRCA1 p.Glu188Asp Uncertain significance ★★ ⚠ same residue
BRCA1 p.Glu188Lys 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
BRCA1 c.212+1G>T Pathogenic ★★★ same condition
BRCA1 c.212+3A>G 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-glu188val (accessed [today's date]).

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