Is BRIP1 p.Pro47Ser (c.139C>T) pathogenic?

BRIP1 p.Pro47Ser (c.139C>T) is classified Uncertain significance in BRIP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-11). AlphaMissense: likely pathogenic (0.8845); Absent from gnomAD v4.1.

How common is BRIP1 p.Pro47Ser (c.139C>T) in the general population?

BRIP1 p.Pro47Ser (c.139C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRIP1 p.Pro47Ser (c.139C>T)?

AlphaMissense predicts likely pathogenic (score 0.8845) — an in-silico prediction, not a clinical call.

BRIP1 p.Pro47Ser

c.139C>T · VCV4082934

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8845 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8845	likely pathogenic
REVEL	0.756	pathogenic-leaning
SaProt	LLR -14.27	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 68 kb · p 0.065 · regional, not allelic
Overall
CADD	28.2	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

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.Pro47Ser
Coding: c.139C>T
MANE Select: NM_032043
Type: single nucleotide variant
Location: chr17:61859862 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.19 · 6 PDB
Residue 47: the helicase atp-binding domain; a UniProt-annotated variant site (in bc; early onset; loss of atpase and helicase activities)

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

Similar variants

BRIP1 p.Pro47Arg Uncertain significance ★★ ⚠ same residue
BRIP1 p.Pro47Thr Uncertain significance ★★ ⚠ same residue
BRIP1 p.Pro47= Benign/Likely benign ★★ same residue
BRIP1 p.Pro47Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
BRIP1 p.Pro47His Uncertain significance ★ ⚠ same residue
BRIP1 p.Pro47fs Pathogenic ★ same residue
BRIP1 c.1140+1G>A Likely pathogenic ★★ same type
BRIP1 c.1141-2A>C Likely pathogenic ★★ same type

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-pro47ser (accessed [today's date]).

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