Is BRIP1 p.Arg855His (c.2564G>A) pathogenic?

BRIP1 p.Arg855His (c.2564G>A) is classified Uncertain significance in BRIP1 (ClinVar, Multiple submitters, 17 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1285); Ultra-rare (popmax 0.0281%, afr); Associated with hereditary breast carcinoma.

What condition is associated with BRIP1 p.Arg855His (c.2564G>A)?

BRIP1 p.Arg855His (c.2564G>A) is associated with hereditary breast carcinoma, hereditary breast ovarian cancer syndrome, ovarian cancer (ClinVar).

How common is BRIP1 p.Arg855His (c.2564G>A) in the general population?

BRIP1 p.Arg855His (c.2564G>A) is ultra-rare (popmax 0.0281%, afr) (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.Arg855His (c.2564G>A)?

AlphaMissense predicts likely benign (score 0.1285) — an in-silico prediction, not a clinical call.

BRIP1 p.Arg855His

c.2564G>A · rs200894063 · VCV128175

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 17 submitters

AlphaMissense

likely benign

0.1285 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0281%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
AlphaMissense	0.1285	likely benign
REVEL	0.534	indeterminate
SaProt	LLR -8.21	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.3	GERP 1.2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 110 kb · p 3.3e-06 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0281% African / African-American · 21/74,862 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0157%

Overall 0.00316% 51/1,612,848 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0281%	3,565
South Asian	0.0165%	6,071
Remaining individualsnot grpmax-eligible	0.0048%	20,816
Admixed American	0.00333%	29,994
European (non-Finnish)	0.000848%	117,907

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.Arg855His
Coding: c.2564G>A
MANE Select: NM_032043
dbSNP: rs200894063
Type: single nucleotide variant
Location: chr17:61693441 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.19 · 6 PDB

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 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.Arg855Cys Uncertain significance ★★ ⚠ same residue
BRIP1 p.Arg855Leu Uncertain significance ★★ ⚠ same residue
BRIP1 p.Arg855Ser Uncertain significance ★★ ⚠ same residue
BRIP1 p.Arg855= Likely benign ★★ same residue
BRIP1 p.Arg855Pro Uncertain significance ★ ⚠ same residue
BRIP1 c.1140+1G>A Likely pathogenic ★★ same condition
BRIP1 c.1141-2A>C Likely pathogenic ★★ same condition
BRIP1 c.1141-2A>G 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-arg855his (accessed [today's date]).

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