Is BRCA1 p.Glu1731Lys (c.5191G>A) pathogenic?

BRCA1 p.Glu1731Lys (c.5191G>A) is classified Uncertain significance in BRCA1 (ClinVar, Expert panel, 7 submitters; last evaluated 2026-01-04). AlphaMissense: likely benign (0.3366); Very rare (popmax 0.00223%, eas); Associated with BRCA1-related cancer predisposition.

What condition is associated with BRCA1 p.Glu1731Lys (c.5191G>A)?

BRCA1 p.Glu1731Lys (c.5191G>A) is associated with BRCA1-related cancer predisposition, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 1 (ClinVar).

How common is BRCA1 p.Glu1731Lys (c.5191G>A) in the general population?

BRCA1 p.Glu1731Lys (c.5191G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about BRCA1 p.Glu1731Lys (c.5191G>A)?

AlphaMissense predicts likely benign (score 0.3366) — an in-silico prediction, not a clinical call.

BRCA1 p.Glu1731Lys

c.5191G>A · rs397507244 · VCV91641

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.3366 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

BRCA1-related cancer predisposition

Computational evidence

Protein change
AlphaMissense	0.3366	likely benign
REVEL	0.586	indeterminate
SaProt	LLR -12.71	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	27.6	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

Grpmax group 0.00223% East Asian · 1/44,858 alleles

Overall 6.86e-05% 1/1,456,706 alleles · very rare

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.

ClinGen expert panel — ENIGMA BRCA1 and BRCA2 VCEP

Uncertain Significance for BRCA1-related cancer predisposition. Applied ACMG criteria (verbatim):

PM2_Supporting PS3 BP4

Curation rationale (ClinGen, verbatim)

The c.5191G>A variant in BRCA1 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 1731 (p.Glu1731Lys). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.13, which is below the recommended threshold of 0.15 for predicting no impact on BRCA1 via protein change. A SpliceAI score of 0.01 predicts no impact on splicing (score threshold ≤0.1) This variant is reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID:30209399). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_supporting, BP4, PS3).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Variant & gene context

Gene: BRCA1
Protein: p.Glu1731Lys
Coding: c.5191G>A
MANE Select: NM_007294
dbSNP: rs397507244
Type: single nucleotide variant
Location: chr17:43063335 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1731: the brct 1 domain; a UniProt-annotated variant site (in fancs); an α-helix

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

Disease context

Also linked: hereditary breast ovarian cancer syndrome breast-ovarian cancer, familial, susceptibility to, 1 hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

BRCA1 p.Glu1731= Likely benign ★★★ same residue
BRCA1 p.Glu1731Ter Pathogenic/Likely pathogenic ★★ same residue
BRCA1 p.Glu1731Asp Uncertain significance ★ ⚠ same residue
BRCA1 p.Glu1731Gly Uncertain significance ★ ⚠ same residue
BRCA1 p.Glu1731fs Pathogenic ★ 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-glu1731lys (accessed [today's date]).

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