Is BRIP1 p.Lys656Met (c.1967A>T) pathogenic?

BRIP1 p.Lys656Met (c.1967A>T) is classified Uncertain significance in BRIP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-05). AlphaMissense: likely benign (0.1213); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BRIP1 p.Lys656Met (c.1967A>T)?

BRIP1 p.Lys656Met (c.1967A>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is BRIP1 p.Lys656Met (c.1967A>T) in the general population?

BRIP1 p.Lys656Met (c.1967A>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about BRIP1 p.Lys656Met (c.1967A>T)?

AlphaMissense predicts likely benign (score 0.1213) — an in-silico prediction, not a clinical call.

BRIP1 p.Lys656Met

c.1967A>T · rs1322017079 · VCV2626401

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1213 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1213	likely benign
REVEL	0.225	benign-leaning
SaProt	LLR -7.25	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.34	GERP -0.33, phastCons 0.3
Regional constraint	o/e 0.84	unconstrained · MANE · 110 kb · p 3.3e-06 · regional, not allelic
Overall
CADD	21.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 8.47e-05% European (non-Finnish) · 1/1,180,012 alleles

Overall 6.84e-05% 1/1,461,840 alleles · very rare

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.Lys656Met
Coding: c.1967A>T
MANE Select: NM_032043
dbSNP: rs1322017079
Type: single nucleotide variant
Location: chr17:61776531 (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

Similar variants

BRIP1 p.Lys656Arg Uncertain significance ★★ ⚠ same residue
BRIP1 p.Lys656Glu Uncertain significance ★ ⚠ same residue
BRIP1 p.Lys656Thr Uncertain significance ★ ⚠ same residue
BRIP1 p.Lys656Ter Pathogenic ★★ same residue
BRIP1 p.Lys656Asn Uncertain significance ★ ⚠ same residue
BRIP1 p.Lys656= Likely benign ★ same residue
BRIP1 c.1140+1G>A Likely pathogenic ★★ same condition
BRIP1 c.1141-2A>G 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-lys656met (accessed [today's date]).

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