Is BRCA1 p.Ala1789Thr (c.5365G>A) pathogenic?

BRCA1 p.Ala1789Thr (c.5365G>A) is classified Likely pathogenic in BRCA1 (ClinVar, Expert panel, 11 submitters; last evaluated 2025-12-02). AlphaMissense: likely pathogenic (0.6958); Very rare (popmax 0.0011%, sas); Associated with BRCA1-related cancer predisposition.

What condition is associated with BRCA1 p.Ala1789Thr (c.5365G>A)?

BRCA1 p.Ala1789Thr (c.5365G>A) is associated with BRCA1-related cancer predisposition, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 1 (ClinVar).

How common is BRCA1 p.Ala1789Thr (c.5365G>A) in the general population?

BRCA1 p.Ala1789Thr (c.5365G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about BRCA1 p.Ala1789Thr (c.5365G>A)?

AlphaMissense predicts likely pathogenic (score 0.6958) — an in-silico prediction, not a clinical call.

BRCA1 p.Ala1789Thr

c.5365G>A · rs80357078 · VCV55552

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 11 submitters

AlphaMissense

likely pathogenic

0.6958 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

BRCA1-related cancer predisposition

Computational evidence

Protein change
AlphaMissense	0.6958	likely pathogenic ✓ concordant with ClinVar · top 6% in BRCA1
REVEL	0.793	moderately pathogenic-leaning
SaProt	LLR -12.37	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 7.6	GERP 2.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	24.8	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 0.0011% South Asian · 1/91,082 alleles

Overall 6.84e-05% 1/1,461,880 alleles · very rare

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.

ClinGen expert panel — ENIGMA BRCA1 and BRCA2 VCEP

Likely Pathogenic for BRCA1-related cancer predisposition. Applied ACMG criteria (verbatim):

PS3 PP3 PP4

Curation rationale (ClinGen, verbatim)

The c.5365G>A variant in BRCA1 is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 1789 (p.(Ala1789Thr)). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:30209399, 32546644, 38709234) (PS3 met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.44, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0 predicts no impact on splicing (score threshold <0.10) (PP3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 3.2 (based on Cosegregation LR=3.2), within the thresholds for supporting evidence towards pathogenicity (LR >2.08 & ≤4.3) (PP4 met; Internal lab contributor). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PS3, PP3, PP4).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Variant & gene context

Gene: BRCA1
Protein: p.Ala1789Thr
Coding: c.5365G>A
MANE Select: NM_007294
dbSNP: rs80357078
Type: single nucleotide variant
Location: chr17:43049162 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1789: a UniProt-annotated variant site (in fancs); the brct 2 domain; 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

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

Similar variants

BRCA1 p.Ala1789= Likely benign ★★ same residue
BRCA1 p.Ala1789Asp Likely pathogenic ★ same residue
BRCA1 p.Ala1789Val Likely pathogenic ★ same residue
BRCA1 p.Ala1789Pro Uncertain significance ★ ⚠ same residue
BRCA1 p.Ala1789Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Ala1789fs 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-ala1789thr (accessed [today's date]).

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