Is BRIP1 p.Ala821Val (c.2462C>T) pathogenic?

BRIP1 p.Ala821Val (c.2462C>T) is classified Uncertain significance in BRIP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-15). AlphaMissense: likely pathogenic (0.9902); Very rare (popmax 0.00167%, amr); Associated with Fanconi anemia complementation group J.

What condition is associated with BRIP1 p.Ala821Val (c.2462C>T)?

BRIP1 p.Ala821Val (c.2462C>T) is associated with Fanconi anemia complementation group J, hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is BRIP1 p.Ala821Val (c.2462C>T) in the general population?

BRIP1 p.Ala821Val (c.2462C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about BRIP1 p.Ala821Val (c.2462C>T)?

AlphaMissense predicts likely pathogenic (score 0.9902) — an in-silico prediction, not a clinical call.

BRIP1 p.Ala821Val

c.2462C>T · rs876658697 · VCV230667

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9902 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Fanconi anemia complementation group J

Computational evidence

Protein change
AlphaMissense	0.9902	likely pathogenic · top 3% in BRIP1
REVEL	0.963	strongly pathogenic-leaning
SaProt	LLR -16.03	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 2.3, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 110 kb · p 3.3e-06 · regional, not allelic
Overall
CADD	29.5	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 0.00167% Admixed American · 1/59,790 alleles

Overall 6.87e-05% 1/1,455,140 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.Ala821Val
Coding: c.2462C>T
MANE Select: NM_032043
dbSNP: rs876658697
Type: single nucleotide variant
Location: chr17:61715981 (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

Fanconi anemia complementation group J — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

BRIP1 p.Ala821Pro Uncertain significance ★★ ⚠ same residue
BRIP1 p.Ala821= Likely benign ★★ same residue
BRIP1 p.Ala821fs Pathogenic ★ 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

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-ala821val (accessed [today's date]).

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