Is BRIP1 p.Pro47Ala (c.139C>G) pathogenic?

BRIP1 p.Pro47Ala (c.139C>G) is classified Conflicting classifications of pathogenicity in BRIP1 (ClinVar, Conflicting submitters, 35 submitters; last evaluated 2026-03-01). AlphaMissense: likely pathogenic (0.7248); Ultra-rare (popmax 0.0456%, nfe); Associated with hereditary breast carcinoma.

What condition is associated with BRIP1 p.Pro47Ala (c.139C>G)?

BRIP1 p.Pro47Ala (c.139C>G) is associated with hereditary breast carcinoma, hereditary breast ovarian cancer syndrome, breast cancer (ClinVar).

How common is BRIP1 p.Pro47Ala (c.139C>G) in the general population?

BRIP1 p.Pro47Ala (c.139C>G) is ultra-rare (popmax 0.0456%, nfe) (gnomAD).

How is Hereditary breast cancer inherited?

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

What do computational predictors say about BRIP1 p.Pro47Ala (c.139C>G)?

AlphaMissense predicts likely pathogenic (score 0.7248) — an in-silico prediction, not a clinical call.

BRIP1 p.Pro47Ala

c.139C>G · rs28903098 · VCV4736

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 35 submitters

AlphaMissense

likely pathogenic

0.7248 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0456%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
AlphaMissense	0.7248	likely pathogenic
REVEL	0.698	pathogenic-leaning
SaProt	LLR -13.25	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 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 68 kb · p 0.065 · regional, not allelic
Overall
CADD	27.1	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 0.0456% European (non-Finnish) · 538/1,179,826 alleles

Filtering AF 0.0424% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0411%

Overall 0.0355% 573/1,613,850 alleles · ultra-rare exomes 538/1,461,574 · genomes 35/152,276 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0456%	2,193
Middle Eastern	0.033%	3,029
Remaining individualsnot grpmax-eligible	0.024%	4,166
Admixed American	0.01%	10,004
African / African-American	0.008%	12,504
South Asian	0.00439%	22,766
Finnishnot grpmax-eligible	0.00312%	32,003

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: BRIP1
Protein: p.Pro47Ala
Coding: c.139C>G
MANE Select: NM_032043
dbSNP: rs28903098
Type: single nucleotide variant
Location: chr17:61859862 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.19 · 6 PDB
Residue 47: the helicase atp-binding domain; a UniProt-annotated variant site (in bc; early onset; loss of atpase and helicase activities)

Full BRIP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: hereditary breast ovarian cancer syndrome breast cancer ovarian cancer Fanconi anemia complementation group J hereditary neoplastic syndrome

For Hereditary breast cancer (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adult, Elderly

Similar variants

BRIP1 p.Pro47Arg Uncertain significance ★★ ⚠ same residue
BRIP1 p.Pro47Thr Uncertain significance ★★ ⚠ same residue
BRIP1 p.Pro47= Benign/Likely benign ★★ same residue
BRIP1 p.Pro47His Uncertain significance ★ ⚠ same residue
BRIP1 p.Pro47fs Pathogenic ★ same residue
BRIP1 p.Pro47Ser Uncertain significance ★★ ⚠ same residue
BRIP1 c.1140+1G>A Likely pathogenic ★★ same condition
BRIP1 c.1141-2A>C 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/brip1-p-pro47ala (accessed [today's date]).

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