Is BRCA1 p.Ser1512Ile (c.4535G>T) pathogenic?

BRCA1 p.Ser1512Ile (c.4535G>T) is classified Benign in BRCA1 (ClinVar, Expert panel, 43 submitters; last evaluated 2015-08-10). AlphaMissense: likely benign (0.1413); Rare (popmax 0.368%, nfe); Associated with breast-ovarian cancer, familial, susceptibility to, 1.

What condition is associated with BRCA1 p.Ser1512Ile (c.4535G>T)?

BRCA1 p.Ser1512Ile (c.4535G>T) is associated with breast-ovarian cancer, familial, susceptibility to, 1, hereditary breast ovarian cancer syndrome, pancreatic cancer, susceptibility to, 4 (ClinVar).

How common is BRCA1 p.Ser1512Ile (c.4535G>T) in the general population?

BRCA1 p.Ser1512Ile (c.4535G>T) is rare (popmax 0.368%, nfe) (gnomAD).

How is Hereditary breast and/or ovarian cancer syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about BRCA1 p.Ser1512Ile (c.4535G>T)?

AlphaMissense predicts likely benign (score 0.1413) — an in-silico prediction, not a clinical call.

BRCA1 p.Ser1512Ile

c.4535G>T · rs1800744 · VCV41826

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 43 submitters

AlphaMissense

likely benign

0.1413 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.368%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

breast-ovarian cancer, familial, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.1413	likely benign
REVEL	0.516	indeterminate
SaProt	LLR -8.06	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 1.9	GERP 0.36, phastCons 0.005
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	18.32	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 0.368% European (non-Finnish) · 4,340/1,180,008 alleles

Filtering AF 0.359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.355%

Overall 0.308% 4,969/1,614,128 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.554%	181
European (non-Finnish)grpmax	0.368%	272
Remaining individualsnot grpmax-eligible	0.272%	368
Middle Eastern	0.198%	505
Admixed American	0.145%	690
Finnishnot grpmax-eligible	0.134%	744
South Asian	0.067%	1,493
African / African-American	0.0653%	1,531

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser1512Ile
Coding: c.4535G>T
MANE Select: NM_007294
dbSNP: rs1800744
Type: single nucleotide variant
Location: chr17:43074471 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1512: a UniProt-annotated variant site (in fancs); a UniProt-annotated variant site (in)

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

Disease context

breast-ovarian cancer, familial, susceptibility to, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast ovarian cancer syndrome pancreatic cancer, susceptibility to, 4 hereditary neoplastic syndrome hereditary breast carcinoma Fanconi anemia, complementation group S BRCA1-related cancer predisposition

For Hereditary breast and/or ovarian cancer syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA1 p.Ser1512Gly Uncertain significance ★★ ⚠ same residue
BRCA1 p.Ser1512Asn Uncertain significance ★ ⚠ same residue
BRCA1 p.Ser1512Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Ser1512fs Pathogenic ★★★ same residue
BRCA1 p.Ser1512Ter Likely 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

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-ser1512ile (accessed [today's date]).

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