Is BRIP1 p.Arg855Ser (c.2563C>A) pathogenic?

BRIP1 p.Arg855Ser (c.2563C>A) is classified Uncertain significance in BRIP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-03-23). AlphaMissense: likely pathogenic (0.5642); Very rare (popmax 0.0011%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with BRIP1 p.Arg855Ser (c.2563C>A)?

BRIP1 p.Arg855Ser (c.2563C>A) is associated with hereditary neoplastic syndrome, Fanconi anemia complementation group J, hereditary breast carcinoma (ClinVar).

How common is BRIP1 p.Arg855Ser (c.2563C>A) in the general population?

BRIP1 p.Arg855Ser (c.2563C>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about BRIP1 p.Arg855Ser (c.2563C>A)?

AlphaMissense predicts likely pathogenic (score 0.5642) — an in-silico prediction, not a clinical call.

BRIP1 p.Arg855Ser

c.2563C>A · rs146031731 · VCV821489

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5642 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.5642	likely pathogenic
REVEL	0.551	indeterminate
SaProt	LLR -8.07	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.47	donor loss, 12 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.5	GERP 2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 110 kb · p 3.3e-06 · regional, not allelic
Overall
CADD	24.6	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 0.0011% South Asian · 1/91,038 alleles

Overall 6.2e-05% 1/1,612,986 alleles · very rare exomes 1/1,460,784 · genomes 0/152,202 · joint denominator

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.Arg855Ser
Coding: c.2563C>A
MANE Select: NM_032043
dbSNP: rs146031731
Type: single nucleotide variant
Location: chr17:61693442 (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 neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Fanconi anemia complementation group J hereditary breast carcinoma

Similar variants

BRIP1 p.Arg855Cys Uncertain significance ★★ ⚠ same residue
BRIP1 p.Arg855His Uncertain significance ★★ ⚠ same residue
BRIP1 p.Arg855Leu 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-arg855ser (accessed [today's date]).

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