Is BRIP1 p.Pro129Ser (c.385C>T) pathogenic?

BRIP1 p.Pro129Ser (c.385C>T) is classified Conflicting classifications of pathogenicity in BRIP1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-07). AlphaMissense: likely benign (0.0812); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with BRIP1 p.Pro129Ser (c.385C>T)?

BRIP1 p.Pro129Ser (c.385C>T) is associated with hereditary neoplastic syndrome, Fanconi anemia complementation group J, hereditary breast carcinoma (ClinVar).

How common is BRIP1 p.Pro129Ser (c.385C>T) in the general population?

BRIP1 p.Pro129Ser (c.385C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRIP1 p.Pro129Ser (c.385C>T)?

AlphaMissense predicts likely benign (score 0.0812) — an in-silico prediction, not a clinical call.

BRIP1 p.Pro129Ser

c.385C>T · rs1555616229 · VCV461168

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0812 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0812	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -5.34	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.33 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.5	GERP 1.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 68 kb · p 0.065 · regional, not allelic
Overall
CADD	16.84	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.Pro129Ser
Coding: c.385C>T
MANE Select: NM_032043
dbSNP: rs1555616229
Type: single nucleotide variant
Location: chr17:61849251 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.19 · 6 PDB
Residue 129: the helicase atp-binding domain; the 'disordered' region

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.Pro129Arg Uncertain significance ★★ ⚠ same residue
BRIP1 p.Pro129Leu Uncertain significance ★★ ⚠ same residue
BRIP1 p.Pro129= Conflicting classifications of pathogenicity ★ same residue
BRIP1 p.Pro129His Uncertain significance ★ ⚠ same residue
BRIP1 p.Pro129_Glu130insTer Pathogenic ★★ same residue
BRIP1 p.Pro129fs Pathogenic ★★ 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-pro129ser (accessed [today's date]).

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