Is BRCA1 p.Arg136Lys (c.407G>A) pathogenic?

BRCA1 p.Arg136Lys (c.407G>A) is classified Uncertain significance in BRCA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-07-20). AlphaMissense: likely benign (0.1065); Ultra-rare (popmax 0.0165%, mid); Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with BRCA1 p.Arg136Lys (c.407G>A)?

BRCA1 p.Arg136Lys (c.407G>A) is associated with hereditary breast ovarian cancer syndrome (ClinVar).

How common is BRCA1 p.Arg136Lys (c.407G>A) in the general population?

BRCA1 p.Arg136Lys (c.407G>A) is ultra-rare (popmax 0.0165%, mid) (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.Arg136Lys (c.407G>A)?

AlphaMissense predicts likely benign (score 0.1065) — an in-silico prediction, not a clinical call.

BRCA1 p.Arg136Lys

c.407G>A · rs1437476481 · VCV1051488

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1065 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.1065	likely benign
REVEL	0.566	indeterminate
SaProt	LLR -5.88	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.28	GERP -2.3, phastCons 0.031
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	13.88	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,060 alleles

Overall 0.000124% 2/1,613,918 alleles · ultra-rare exomes 2/1,461,784 · genomes 0/152,134 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
European (non-Finnish)	8.47e-05%	1,179,967

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.Arg136Lys
Coding: c.407G>A
MANE Select: NM_007294
dbSNP: rs1437476481
Type: single nucleotide variant
Location: chr17:43104156 (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

hereditary breast ovarian cancer syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

BRCA1 p.Arg136Gly Uncertain significance ★ ⚠ same residue
BRCA1 p.Arg136= Likely benign ★ same residue
BRCA1 p.Arg136fs Pathogenic ★★★ same residue
BRCA1 p.Arg136Thr Uncertain significance ★ ⚠ 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

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-arg136lys (accessed [today's date]).

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