Is BRCA1 p.Ser1387Pro (c.4159T>C) pathogenic?

BRCA1 p.Ser1387Pro (c.4159T>C) is classified Likely benign in BRCA1 (ClinVar, Expert panel, 10 submitters; last evaluated 2025-05-23). AlphaMissense: likely benign (0.1618); Very rare (popmax 0.00017%, nfe); Associated with BRCA1-related cancer predisposition.

What condition is associated with BRCA1 p.Ser1387Pro (c.4159T>C)?

BRCA1 p.Ser1387Pro (c.4159T>C) is associated with BRCA1-related cancer predisposition, hereditary breast ovarian cancer syndrome, ovarian cancer (ClinVar).

How common is BRCA1 p.Ser1387Pro (c.4159T>C) in the general population?

BRCA1 p.Ser1387Pro (c.4159T>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about BRCA1 p.Ser1387Pro (c.4159T>C)?

AlphaMissense predicts likely benign (score 0.1618) — an in-silico prediction, not a clinical call.

BRCA1 p.Ser1387Pro

c.4159T>C · rs876658221 · VCV224433

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.1618 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

BRCA1-related cancer predisposition

ClinGen expert panel — ENIGMA BRCA1 and BRCA2 VCEP

Likely Benign for BRCA1-related cancer predisposition. Applied ACMG criteria (verbatim):

BP1_Strong BP5

Curation rationale (ClinGen, verbatim)

The c.4159T>C variant in BRCA1 is a missense variant predicted to cause substitution of serine by proline at amino acid 1387 (p.Ser1387Pro). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using SpliceAI (score 0.00, score threshold ≤0.1) (BP1_Strong met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.364 (based on Family History LR=0.364), within the thresholds for supporting benign evidence (LR >0.23 & ≤0.48) (BP5 met; PMID 31853058). In summary, this variant meets the criteria to be classified as a likely benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BP1_Strong, BP5).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.1618	likely benign
REVEL	0.481	indeterminate
SaProt	LLR -9.38	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.8	GERP 2.2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	24.4	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

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,284 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,612,348 alleles · very rare exomes 2/1,460,024 · genomes 0/152,324 · joint denominator

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: BRCA1
Protein: p.Ser1387Pro
Coding: c.4159T>C
MANE Select: NM_007294
dbSNP: rs876658221
Type: single nucleotide variant
Location: chr17:43090970 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1387: a UniProt-annotated variant site (in fancs); a modified residue (phosphoserine; by atm and atr); the 'disordered' region

Full BRCA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: hereditary breast ovarian cancer syndrome ovarian cancer breast-ovarian cancer, familial, susceptibility to, 1 hereditary neoplastic syndrome breast neoplasm

Similar variants

BRCA1 p.Ser1387Cys Uncertain significance ★★ ⚠ same residue
BRCA1 p.Ser1387Phe Uncertain significance ★ ⚠ same residue
BRCA1 p.Ser1387fs 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-ser1387pro (accessed [today's date]).

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