Is BRCA1 p.Cys64Arg (c.190T>C) pathogenic?

BRCA1 p.Cys64Arg (c.190T>C) is classified Pathogenic in BRCA1 (ClinVar, Multiple submitters, 20 submitters; last evaluated 2026-04-24). AlphaMissense: likely pathogenic (0.9965); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA1 p.Cys64Arg (c.190T>C)?

BRCA1 p.Cys64Arg (c.190T>C) is associated with hereditary neoplastic syndrome, gastric cancer, hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA1 p.Cys64Arg (c.190T>C) in the general population?

BRCA1 p.Cys64Arg (c.190T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRCA1 p.Cys64Arg (c.190T>C)?

AlphaMissense predicts likely pathogenic (score 0.9965) — an in-silico prediction, not a clinical call.

BRCA1 p.Cys64Arg

c.190T>C · rs80357064 · VCV54394

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 20 submitters

AlphaMissense

likely pathogenic

0.9965 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,602,460)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9965	likely pathogenic ✓ concordant with ClinVar · top 1% in BRCA1
REVEL	0.938	strongly pathogenic-leaning
SaProt	LLR -16.36	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.65 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	26.5	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

No allele count reported in gnomAD v4.1 (AN 1,602,460). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: BRCA1
Protein: p.Cys64Arg
Coding: c.190T>C
MANE Select: NM_007294
dbSNP: rs80357064
Type: single nucleotide variant
Location: chr17:43106478 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 64: a β-strand; a UniProt-annotated variant site (in bc; no interaction with bap1); a UniProt-annotated variant site (in bc; pathogenic)

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: gastric cancer hereditary breast ovarian cancer syndrome breast-ovarian cancer, familial, susceptibility to, 1 hereditary breast carcinoma

Similar variants

BRCA1 p.Cys64Ter Pathogenic ★★★ same residue
BRCA1 p.Cys64Tyr Pathogenic ★★★ same residue
BRCA1 p.Cys64Gly Pathogenic ★★ same residue
BRCA1 p.Cys64Ser Pathogenic/Likely pathogenic ★★ same residue
BRCA1 p.Cys64Trp Pathogenic/Likely pathogenic ★★ same residue
BRCA1 p.Cys64fs 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-cys64arg (accessed [today's date]).

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