Is BRCA1 p.Asp1739Tyr (c.5215G>T) pathogenic?

BRCA1 p.Asp1739Tyr (c.5215G>T) is classified Pathogenic/Likely pathogenic in BRCA1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-10). AlphaMissense: likely pathogenic (0.9504); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA1 p.Asp1739Tyr (c.5215G>T)?

BRCA1 p.Asp1739Tyr (c.5215G>T) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 1 (ClinVar).

How common is BRCA1 p.Asp1739Tyr (c.5215G>T) in the general population?

BRCA1 p.Asp1739Tyr (c.5215G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRCA1 p.Asp1739Tyr (c.5215G>T)?

AlphaMissense predicts likely pathogenic (score 0.9504) — an in-silico prediction, not a clinical call.

BRCA1 p.Asp1739Tyr

c.5215G>T · rs80357283 · VCV55464

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9504 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9504	likely pathogenic ✓ concordant with ClinVar · top 2% in BRCA1
REVEL	0.771	pathogenic-leaning
SaProt	LLR -15.62	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	25.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BRCA1
Protein: p.Asp1739Tyr
Coding: c.5215G>T
MANE Select: NM_007294
dbSNP: rs80357283
Type: single nucleotide variant
Location: chr17:43057114 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1739: a UniProt-annotated variant site (in fancs); a UniProt-annotated variant site (in bc; uncertain significance; functionally impaired in vitro)

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

Similar variants

BRCA1 p.Asp1739Asn Likely benign ★★★ ⚠ same residue
BRCA1 p.Asp1739Gly Pathogenic/Likely pathogenic ★★ same residue
BRCA1 p.Asp1739Val Pathogenic/Likely pathogenic ★★ same residue
BRCA1 p.Asp1739Glu Likely pathogenic ★ same residue
BRCA1 p.Asp1739His Likely pathogenic ★ same residue
BRCA1 p.Asp1739fs 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-asp1739tyr (accessed [today's date]).

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