Is BRIP1 p.Arg581Ter (c.1741C>T) pathogenic?

BRIP1 p.Arg581Ter (c.1741C>T) is classified Pathogenic in BRIP1 (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-05-05). Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with BRIP1 p.Arg581Ter (c.1741C>T)?

BRIP1 p.Arg581Ter (c.1741C>T) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, Fanconi anemia complementation group D2 (ClinVar).

How common is BRIP1 p.Arg581Ter (c.1741C>T) in the general population?

BRIP1 p.Arg581Ter (c.1741C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

BRIP1 p.Arg581Ter

c.1741C>T · rs780020495 · VCV434539

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 12 of 20
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP -0.23, phastCons 1
Overall
CADD	41.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,880 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000958% 14/1,461,848 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,880
Admixed American	0.00167%	60,024
African / African-American	0.00133%	75,036
South Asian	0.0011%	91,082
European (non-Finnish)	0.000847%	118,000

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.Arg581Ter
Coding: c.1741C>T
MANE Select: NM_032043
dbSNP: rs780020495
Type: single nucleotide variant
Location: chr17:61780893 (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: hereditary breast ovarian cancer syndrome Fanconi anemia complementation group D2 Fanconi anemia complementation group J hereditary breast carcinoma ovarian neoplasm

Similar variants

BRIP1 p.Arg581Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
BRIP1 p.Arg581del Uncertain significance ★ same residue
BACH1 p.Cys581Arg 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
BRIP1 c.1141-2A>T Likely pathogenic ★★ same condition
BRIP1 c.1340+1G>A Pathogenic/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-arg581ter (accessed [today's date]).

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