Is BRIP1 p.Ile746Val (c.2236A>G) pathogenic?

BRIP1 p.Ile746Val (c.2236A>G) is classified Benign/Likely benign in BRIP1 (ClinVar, Multiple submitters, 21 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.061); Low-frequency (popmax 1.47%, afr); Associated with Breast and/or ovarian cancer.

What condition is associated with BRIP1 p.Ile746Val (c.2236A>G)?

BRIP1 p.Ile746Val (c.2236A>G) is associated with Breast and/or ovarian cancer, hereditary breast ovarian cancer syndrome, breast cancer (ClinVar).

How common is BRIP1 p.Ile746Val (c.2236A>G) in the general population?

BRIP1 p.Ile746Val (c.2236A>G) is low-frequency (popmax 1.47%, afr) (gnomAD).

What do computational predictors say about BRIP1 p.Ile746Val (c.2236A>G)?

AlphaMissense predicts likely benign (score 0.061) — an in-silico prediction, not a clinical call.

BRIP1 p.Ile746Val

c.2236A>G · rs111536363 · VCV133751

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 21 submitters

AlphaMissense

likely benign

0.061 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.47%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Breast and/or ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.061	likely benign
REVEL	0.164	moderately benign-leaning
SaProt	LLR -6.40	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4	GERP -2.7
Regional constraint	o/e 0.84	unconstrained · MANE · 110 kb · p 3.3e-06 · regional, not allelic
Overall
CADD	2.423	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 1.47% African / African-American · 1,103/75,046 alleles

Filtering AF 1.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.37%

Overall 0.0769% 1,241/1,613,952 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.47%	68
Middle Eastern	0.149%	673
Remaining individualsnot grpmax-eligible	0.104%	961
Admixed American	0.0716%	1,396
South Asian	0.00549%	18,211
East Asian	0.00223%	44,824
European (non-Finnish)	0.00127%	78,660

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.Ile746Val
Coding: c.2236A>G
MANE Select: NM_032043
dbSNP: rs111536363
Type: single nucleotide variant
Location: chr17:61744453 (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

Breast and/or ovarian cancer — 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 hereditary breast carcinoma

Similar variants

BRIP1 p.Ile746= Likely benign ★★ same residue
BRIP1 p.Ile746fs Pathogenic ★★ 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
BRIP1 c.1341-1G>A 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-ile746val (accessed [today's date]).

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