Is BRIP1 p.Leu415Phe (c.1243C>T) pathogenic?

BRIP1 p.Leu415Phe (c.1243C>T) is classified Uncertain significance in BRIP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-24). AlphaMissense: ambiguous (0.3979); Absent from gnomAD v4.1; Associated with hereditary breast carcinoma.

What condition is associated with BRIP1 p.Leu415Phe (c.1243C>T)?

BRIP1 p.Leu415Phe (c.1243C>T) is associated with hereditary breast carcinoma, Fanconi anemia complementation group J (ClinVar).

How common is BRIP1 p.Leu415Phe (c.1243C>T) in the general population?

BRIP1 p.Leu415Phe (c.1243C>T) is absent from gnomAD v4.1 (gnomAD).

How is Hereditary breast cancer inherited?

Typically Autosomal dominant, Multigenic/multifactorial (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about BRIP1 p.Leu415Phe (c.1243C>T)?

AlphaMissense predicts ambiguous (score 0.3979) — an in-silico prediction, not a clinical call.

BRIP1 p.Leu415Phe

c.1243C>T · VCV4794639

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3979 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
AlphaMissense	0.3979	ambiguous
REVEL	0.708	pathogenic-leaning
SaProt	LLR -11.41	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 68 kb · p 0.065 · regional, not allelic
Overall
CADD	28.0	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.Leu415Phe
Coding: c.1243C>T
MANE Select: NM_032043
Type: single nucleotide variant
Location: chr17:61799197 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.19 · 6 PDB
Residue 415: the helicase atp-binding domain

Full BRIP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary breast carcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Fanconi anemia complementation group J

For Hereditary breast cancer (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adult, Elderly

Similar variants

BACH1 p.Gln415Arg Uncertain significance ★ ⚠ same residue
BRIP1 p.Leu415Pro 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
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-leu415phe (accessed [today's date]).

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