Is BRCA1 p.Ser1056Pro (c.3166T>C) pathogenic?

BRCA1 p.Ser1056Pro (c.3166T>C) is classified Conflicting classifications of pathogenicity in BRCA1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-09-13). AlphaMissense: likely benign (0.2178); Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA1 p.Ser1056Pro (c.3166T>C)?

BRCA1 p.Ser1056Pro (c.3166T>C) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA1 p.Ser1056Pro (c.3166T>C) in the general population?

BRCA1 p.Ser1056Pro (c.3166T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about BRCA1 p.Ser1056Pro (c.3166T>C)?

AlphaMissense predicts likely benign (score 0.2178) — an in-silico prediction, not a clinical call.

BRCA1 p.Ser1056Pro

c.3166T>C · rs876659601 · VCV232179

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2178 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2178	likely benign
REVEL	0.535	indeterminate
SaProt	LLR -10.06	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.3	GERP -1.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	22.7	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 0.00223% East Asian · 1/44,868 alleles

Overall 0.000124% 2/1,613,784 alleles · very rare exomes 1/1,461,696 · genomes 1/152,088 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,868
European (non-Finnish)	8.47e-05%	1,179,976

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.Ser1056Pro
Coding: c.3166T>C
MANE Select: NM_007294
dbSNP: rs876659601
Type: single nucleotide variant
Location: chr17:43092365 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1056: a UniProt-annotated variant site (in fancs)

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.Ser1056Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Ser1056Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Ser1056Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Ser1056Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Ser1056= Likely benign ★ same residue
BRCA1 p.Ser1056fs Pathogenic ★ same residue
BRCA1 c.134+3A>T Likely pathogenic ★★★ same condition
BRCA1 c.135-1G>T 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-ser1056pro (accessed [today's date]).

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