Is BRCA1 p.Pro1812Ser (c.5434C>T) pathogenic?

BRCA1 p.Pro1812Ser (c.5434C>T) is classified Conflicting classifications of pathogenicity in BRCA1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-05-19). AlphaMissense: ambiguous (0.3751); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA1 p.Pro1812Ser (c.5434C>T)?

BRCA1 p.Pro1812Ser (c.5434C>T) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA1 p.Pro1812Ser (c.5434C>T) in the general population?

BRCA1 p.Pro1812Ser (c.5434C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRCA1 p.Pro1812Ser (c.5434C>T)?

AlphaMissense predicts ambiguous (score 0.3751) — an in-silico prediction, not a clinical call.

BRCA1 p.Pro1812Ser

c.5434C>T · rs1800751 · VCV865501

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3751 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3751	ambiguous
REVEL	0.514	indeterminate
SaProt	LLR -3.15	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 2.5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	22.8	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.Pro1812Ser
Coding: c.5434C>T
MANE Select: NM_007294
dbSNP: rs1800751
Type: single nucleotide variant
Location: chr17:43047676 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1812: a UniProt-annotated variant site (in fancs); the brct 2 domain; a UniProt-annotated variant site (in bc; uncertain significance; functionally neutral in vitro); a UniProt-annotated variant site (in ovarian cancer; uncertain significance); an α-helix

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

Also linked: hereditary breast ovarian cancer syndrome

Similar variants

BRCA1 p.Pro1812Ala Pathogenic/Likely pathogenic ★★ ⚠ same residue
BRCA1 p.Pro1812= Likely benign ★ same residue
BRCA1 p.Pro1812fs Pathogenic ★ 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
BRCA1 c.212+1G>T Pathogenic ★★★ same condition
BRCA1 c.212+3A>G 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-pro1812ser (accessed [today's date]).

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