Is BRIP1 p.Gln40Pro (c.119A>C) pathogenic?

BRIP1 p.Gln40Pro (c.119A>C) is classified Uncertain significance in BRIP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-06-16). AlphaMissense: likely pathogenic (0.857); Very rare (popmax 0.0011%, sas); Associated with Fanconi anemia complementation group J.

What condition is associated with BRIP1 p.Gln40Pro (c.119A>C)?

BRIP1 p.Gln40Pro (c.119A>C) is associated with Fanconi anemia complementation group J, hereditary breast carcinoma (ClinVar).

How common is BRIP1 p.Gln40Pro (c.119A>C) in the general population?

BRIP1 p.Gln40Pro (c.119A>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about BRIP1 p.Gln40Pro (c.119A>C)?

AlphaMissense predicts likely pathogenic (score 0.857) — an in-silico prediction, not a clinical call.

BRIP1 p.Gln40Pro

c.119A>C · rs2078951315 · VCV1020978

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.857 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Fanconi anemia complementation group J

Computational evidence

Protein change
AlphaMissense	0.857	likely pathogenic
REVEL	0.471	indeterminate
SaProt	LLR -13.87	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 68 kb · p 0.065 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0011% South Asian · 1/91,072 alleles

Overall 0.000124% 2/1,613,512 alleles · very rare exomes 2/1,461,176 · genomes 0/152,336 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,480
South Asiangrpmax	0.0011%	91,072

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Gln40Pro
Coding: c.119A>C
MANE Select: NM_032043
dbSNP: rs2078951315
Type: single nucleotide variant
Location: chr17:61859882 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.19 · 6 PDB
Residue 40: the helicase atp-binding domain

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: hereditary breast carcinoma

Similar variants

BRIP1 p.Gln40Ter Pathogenic/Likely pathogenic ★★ same residue
BRIP1 p.Gln40Arg Uncertain significance ★★ ⚠ same residue
BRIP1 p.Gln40= Benign/Likely benign ★★ same residue
BRIP1 p.Gln40Glu Uncertain significance ★ ⚠ same residue
BRIP1 p.Gln40Lys Uncertain significance ★ ⚠ same residue
BACH1 p.Val40Leu Uncertain significance ★ ⚠ same residue
BRIP1 c.1140+1G>A Likely pathogenic ★★ same condition
BRIP1 c.1141-2A>C 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-gln40pro (accessed [today's date]).

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