Is BRCA1 p.Met18Leu (c.52A>C) pathogenic?

BRCA1 p.Met18Leu (c.52A>C) is classified Likely benign in BRCA1 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-12-26). AlphaMissense: ambiguous (0.4944); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA1 p.Met18Leu (c.52A>C)?

BRCA1 p.Met18Leu (c.52A>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is BRCA1 p.Met18Leu (c.52A>C) in the general population?

BRCA1 p.Met18Leu (c.52A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRCA1 p.Met18Leu (c.52A>C)?

AlphaMissense predicts ambiguous (score 0.4944) — an in-silico prediction, not a clinical call.

BRCA1 p.Met18Leu

c.52A>C · rs2055727017 · VCV865041

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4944 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4944	ambiguous · top 9% in BRCA1
REVEL	0.602	indeterminate
SaProt	LLR -4.32	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	22.4	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: BRCA1
Protein: p.Met18Leu
Coding: c.52A>C
MANE Select: NM_007294
dbSNP: rs2055727017
Type: single nucleotide variant
Location: chr17:43124045 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 18: an α-helix; a UniProt-annotated variant site (in bc; pathogenic)

Full BRCA1 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

BRCA1 p.Met18Thr Pathogenic ★★★ same residue
BRCA1 p.Met18Lys Pathogenic/Likely pathogenic ★★ same residue
BRCA1 p.Met18Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Met18Arg Likely pathogenic ★★ same residue
BRCA1 p.Met18Val Uncertain significance ★ ⚠ same residue
BRCA1 c.134+3A>T Likely pathogenic ★★★ same condition
BRCA1 c.135-1G>T Pathogenic ★★★ same condition
BRCA1 c.212+1G>A 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/brca1-p-met18leu (accessed [today's date]).

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