Is BRIP1 p.Val516Glu (c.1547T>A) pathogenic?

BRIP1 p.Val516Glu (c.1547T>A) is classified Uncertain significance in BRIP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-15). AlphaMissense: ambiguous (0.3585); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with BRIP1 p.Val516Glu (c.1547T>A)?

BRIP1 p.Val516Glu (c.1547T>A) is associated with hereditary neoplastic syndrome, Fanconi anemia complementation group J, hereditary breast carcinoma (ClinVar).

How common is BRIP1 p.Val516Glu (c.1547T>A) in the general population?

BRIP1 p.Val516Glu (c.1547T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRIP1 p.Val516Glu (c.1547T>A)?

AlphaMissense predicts ambiguous (score 0.3585) — an in-silico prediction, not a clinical call.

BRIP1 p.Val516Glu

c.1547T>A · rs2077670264 · VCV1041286

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3585 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3585	ambiguous
REVEL	0.503	indeterminate
SaProt	LLR -6.93	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 110 kb · p 3.3e-06 · regional, not allelic
Overall
CADD	25.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BRIP1
Protein: p.Val516Glu
Coding: c.1547T>A
MANE Select: NM_032043
dbSNP: rs2077670264
Type: single nucleotide variant
Location: chr17:61784351 (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.Val516Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
BRIP1 p.Val516= Benign ★ 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-val516glu (accessed [today's date]).

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