Is BRCA1 c.5152+4A>G pathogenic?

BRCA1 c.5152+4A>G is classified Pathogenic/Likely pathogenic in BRCA1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-05-01). Very rare (popmax 8.5e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA1 c.5152+4A>G?

BRCA1 c.5152+4A>G is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 1 (ClinVar).

How common is BRCA1 c.5152+4A>G in the general population?

BRCA1 c.5152+4A>G is very rare (popmax 8.5e-05%, nfe) (gnomAD).

BRCA1 c.5152+4A>G

rs397509232 · VCV55426

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
Splice region	donor +4	donor splice region (+4, within the first 6 intronic nt) · inside the BP7-excluded zone
SpliceAI	Δ0.80	donor loss, 4 bp away · raw score · deltas
Pangolin	Δ0.79	loss · gain 0.02 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.8	GERP 2.7, phastCons 1
Non-coding constraint	Z 1.46	1 kb window · o/e 0.89 · regional · uncalibrated
Overall
CADD	17.13	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.5e-05% European (non-Finnish) · 1/1,176,268 alleles

Overall 6.86e-05% 1/1,457,702 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.

Variant & gene context

Gene: BRCA1
Coding: c.5152+4A>G
MANE Select: NM_007294
dbSNP: rs397509232
Type: single nucleotide variant
Location: chr17:43063870 (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

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

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

Similar variants

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
BRCA1 c.213-12A>G Pathogenic ★★★ same condition
BRCA1 c.213-15A>G Likely pathogenic ★★★ same condition
BRCA1 c.302-1G>C 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-c-5152-plus-4a-g (accessed [today's date]).

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