Is BRCA1 p.Cys61Tyr (c.182G>A) pathogenic?

BRCA1 p.Cys61Tyr (c.182G>A) is classified Pathogenic in BRCA1 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-05-19). AlphaMissense: likely pathogenic (0.9922); Very rare (popmax 0.00111%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA1 p.Cys61Tyr (c.182G>A)?

BRCA1 p.Cys61Tyr (c.182G>A) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, breast-ovarian cancer, familial, susceptibility to, 1 (ClinVar).

How common is BRCA1 p.Cys61Tyr (c.182G>A) in the general population?

BRCA1 p.Cys61Tyr (c.182G>A) is very rare (popmax 0.00111%, sas) (gnomAD).

What do computational predictors say about BRCA1 p.Cys61Tyr (c.182G>A)?

AlphaMissense predicts likely pathogenic (score 0.9922) — an in-silico prediction, not a clinical call.

BRCA1 p.Cys61Tyr

c.182G>A · rs80357093 · VCV54364

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely pathogenic

0.9922 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9922	likely pathogenic ✓ concordant with ClinVar · top 1% in BRCA1
REVEL	0.96	strongly pathogenic-leaning
SaProt	LLR -10.57	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.25	donor gain · deltas
Pangolin	Δ0.68	gain · loss 0.36 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	32.0	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

Grpmax group 0.00111% South Asian · 1/90,372 alleles

Overall 0.000138% 2/1,452,504 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	62,118
South Asiangrpmax	0.00111%	90,372

Remaining individuals 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.Cys61Tyr
Coding: c.182G>A
MANE Select: NM_007294
dbSNP: rs80357093
Type: single nucleotide variant
Location: chr17:43106486 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 61: a UniProt-annotated variant site (in bc and oc; pathogenic; no interaction with bap1)

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.Cys61Gly Pathogenic ★★★ same residue
BRCA1 p.Cys61Arg Pathogenic/Likely pathogenic ★★ same residue
BRCA1 p.Cys61Ser Pathogenic ★★ same residue
BRCA1 p.Cys61= Likely benign ★★ same residue
BRCA1 p.Cys61fs Pathogenic ★★★ same residue
BRCA1 p.Cys61Phe Uncertain significance ★ ⚠ 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-cys61tyr (accessed [today's date]).

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