Is BRCA1 p.Asn1819Ser (c.5456A>G) pathogenic?

BRCA1 p.Asn1819Ser (c.5456A>G) is classified Benign/Likely benign in BRCA1 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0566); Ultra-rare (popmax 0.0178%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA1 p.Asn1819Ser (c.5456A>G)?

BRCA1 p.Asn1819Ser (c.5456A>G) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 1 (ClinVar).

How common is BRCA1 p.Asn1819Ser (c.5456A>G) in the general population?

BRCA1 p.Asn1819Ser (c.5456A>G) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about BRCA1 p.Asn1819Ser (c.5456A>G)?

AlphaMissense predicts likely benign (score 0.0566) — an in-silico prediction, not a clinical call.

BRCA1 p.Asn1819Ser

c.5456A>G · rs80357286 · VCV55585

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

AlphaMissense

likely benign

0.0566 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0566	likely benign
REVEL	0.421	indeterminate
SaProt	LLR -4.01	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1	GERP -4.9
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	0.059	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 0.0178% East Asian · 8/44,898 alleles

Filtering AF 0.00883% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.00657% 106/1,614,076 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,612
European (non-Finnish)	0.00797%	12,554
Remaining individualsnot grpmax-eligible	0.0032%	31,242
Admixed American	0.00167%	60,000
African / African-American	0.00133%	74,934

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.Asn1819Ser
Coding: c.5456A>G
MANE Select: NM_007294
dbSNP: rs80357286
Type: single nucleotide variant
Location: chr17:43047654 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1819: a UniProt-annotated variant site (in fancs); the brct 2 domain; 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 breast-ovarian cancer, familial, susceptibility to, 1 familial pancreatic carcinoma

Similar variants

BRCA1 p.Asn1819Lys Uncertain significance ★★ ⚠ same residue
BRCA1 p.Asn1819= Likely benign ★★ same residue
BRCA1 p.Asn1819Tyr 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
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-asn1819ser (accessed [today's date]).

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