Is BRCA1 p.Ala221Ser (c.661G>T) pathogenic?

BRCA1 p.Ala221Ser (c.661G>T) is classified Conflicting classifications of pathogenicity in BRCA1 (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-04-27). AlphaMissense: likely benign (0.0876); Very rare (popmax 0.00907%, nfe); Associated with Inherited breast cancer and ovarian cancer.

What condition is associated with BRCA1 p.Ala221Ser (c.661G>T)?

BRCA1 p.Ala221Ser (c.661G>T) is associated with Inherited breast cancer and ovarian cancer, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 1 (ClinVar).

How common is BRCA1 p.Ala221Ser (c.661G>T) in the general population?

BRCA1 p.Ala221Ser (c.661G>T) is very rare (popmax 0.00907%, nfe) (gnomAD).

What do computational predictors say about BRCA1 p.Ala221Ser (c.661G>T)?

AlphaMissense predicts likely benign (score 0.0876) — an in-silico prediction, not a clinical call.

BRCA1 p.Ala221Ser

c.661G>T · rs80357088 · VCV37690

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.0876 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00907%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inherited breast cancer and ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.0876	likely benign
REVEL	0.565	indeterminate
SaProt	LLR -5.16	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 -0.44	GERP -3.9, phastCons 0.011
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	12.05	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 0.00907% European (non-Finnish) · 107/1,179,418 alleles

Filtering AF 0.00766% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00709%

Overall 0.00688% 111/1,613,026 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00907%	11,023
Remaining individualsnot grpmax-eligible	0.0032%	31,226
African / African-American	0.00267%	37,427

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.Ala221Ser
Coding: c.661G>T
MANE Select: NM_007294
dbSNP: rs80357088
Type: single nucleotide variant
Location: chr17:43095855 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB

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

Disease context

Inherited breast cancer and ovarian cancer

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

Similar variants

BRCA1 p.Ala221Val Uncertain significance ★★ ⚠ same residue
BRCA1 p.Ala221= Benign/Likely benign ★★ same residue
BRCA1 p.Ala221Glu Uncertain significance ★ ⚠ same residue
BRCA1 p.Ala221Gly Uncertain significance ★ ⚠ same residue
BRCA1 p.Ala221Thr Likely benign ★ 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-ala221ser (accessed [today's date]).

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