Is BRCC3 p.Met59Val (c.175A>G) pathogenic?

BRCC3 p.Met59Val (c.175A>G) is classified Uncertain significance in BRCC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-01). AlphaMissense: likely benign (0.0757); Absent from gnomAD v4.1.

How common is BRCC3 p.Met59Val (c.175A>G) in the general population?

BRCC3 p.Met59Val (c.175A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRCC3 p.Met59Val (c.175A>G)?

AlphaMissense predicts likely benign (score 0.0757) — an in-silico prediction, not a clinical call.

BRCC3 p.Met59Val

c.175A>G · rs2524053734 · VCV2661873

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0757 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0757	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -5.15	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.6	GERP -1.3, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 7,112 bp · p 0.0003 · regional, not allelic
Overall
CADD	9.386	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

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: BRCC3
Protein: p.Met59Val
Coding: c.175A>G
MANE Select: NM_001018055
dbSNP: rs2524053734
Type: single nucleotide variant
Location: chrX:155073411 (GRCh38)
Structure: AlphaFold pLDDT 84.68 · 12 PDB
Residue 59: the mpn domain

Full BRCC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BRCC3 p.Val202Ala Uncertain significance ★★ ⚠ same type
BRCC3 p.Gln147Arg Uncertain significance ★ ⚠ same type
BRCC3 p.Ile187Met Uncertain significance ★ ⚠ same type
BRCC3 p.Leu273Phe Uncertain significance ★ ⚠ same type
BRCC3 p.Thr46Lys Uncertain significance ★ ⚠ same type
BRCC3 c.403+205A>G Likely benign ★ same type
BRCC3 c.681-9A>G Benign ★ same type
BRCC3 p.Ser227= Likely benign ★ 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/brcc3-p-met59val (accessed [today's date]).

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