Is BRCA1 p.Arg78Ile (c.233G>T) pathogenic?

BRCA1 p.Arg78Ile (c.233G>T) is classified Conflicting classifications of pathogenicity in BRCA1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-04-22). AlphaMissense: likely pathogenic (0.668); Absent from gnomAD v4.1; Associated with breast-ovarian cancer, familial, susceptibility to, 1.

How common is BRCA1 p.Arg78Ile (c.233G>T) in the general population?

BRCA1 p.Arg78Ile (c.233G>T) is absent from gnomAD v4.1 (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.Arg78Ile (c.233G>T)?

AlphaMissense predicts likely pathogenic (score 0.668) — an in-silico prediction, not a clinical call.

BRCA1 p.Arg78Ile

Q: What condition is associated with BRCA1 p.Arg78Ile (c.233G>T)?

BRCA1 p.Arg78Ile (c.233G>T) is associated with breast-ovarian cancer, familial, susceptibility to, 1, hereditary neoplastic syndrome (ClinVar).

c.233G>T · rs2054692582 · VCV865587

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.668 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

breast-ovarian cancer, familial, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.668	likely pathogenic · top 7% in BRCA1
REVEL	0.771	pathogenic-leaning
SaProt	LLR -5.64	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.22	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	26.2	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.Arg78Ile
Coding: c.233G>T
MANE Select: NM_007294
dbSNP: rs2054692582
Type: single nucleotide variant
Location: chr17:43104936 (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

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

Also linked: hereditary neoplastic syndrome

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA1 p.Arg78Lys Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Arg78fs 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
BRCA1 c.212+1G>T Pathogenic ★★★ same condition
BRCA1 c.212+3A>G Pathogenic ★★★ same condition
BRCA1 c.213-12A>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-arg78ile (accessed [today's date]).

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