Is BRIP1 p.Val720Met (c.2158G>A) pathogenic?

BRIP1 p.Val720Met (c.2158G>A) is classified Uncertain significance in BRIP1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-07-21). AlphaMissense: likely benign (0.1156); Very rare (popmax 0.00223%, eas); Associated with Fanconi anemia complementation group J.

What condition is associated with BRIP1 p.Val720Met (c.2158G>A)?

BRIP1 p.Val720Met (c.2158G>A) is associated with Fanconi anemia complementation group J, breast cancer, hereditary neoplastic syndrome (ClinVar).

How common is BRIP1 p.Val720Met (c.2158G>A) in the general population?

BRIP1 p.Val720Met (c.2158G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about BRIP1 p.Val720Met (c.2158G>A)?

AlphaMissense predicts likely benign (score 0.1156) — an in-silico prediction, not a clinical call.

BRIP1 p.Val720Met

c.2158G>A · rs1555591459 · VCV491433

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1156 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Fanconi anemia complementation group J

Computational evidence

Protein change
AlphaMissense	0.1156	likely benign
REVEL	0.432	indeterminate
SaProt	LLR -9.05	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.54, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 110 kb · p 3.3e-06 · regional, not allelic
Overall
CADD	23.1	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 0.00223% East Asian · 1/44,834 alleles

Overall 6.2e-05% 1/1,613,864 alleles · very rare exomes 1/1,461,610 · genomes 0/152,254 · 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.Val720Met
Coding: c.2158G>A
MANE Select: NM_032043
dbSNP: rs1555591459
Type: single nucleotide variant
Location: chr17:61744531 (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

Fanconi anemia complementation group J — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: breast cancer hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

BRIP1 p.Val720Leu Uncertain significance ★★ ⚠ same residue
BRIP1 p.Val720= Benign/Likely benign ★★ same residue
BRIP1 p.Val720del Uncertain significance ★★ same residue
BRIP1 p.Val720Ala 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

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-val720met (accessed [today's date]).

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