Is BRCA1 p.Arg7His (c.20G>A) pathogenic?

BRCA1 p.Arg7His (c.20G>A) is classified Conflicting classifications of pathogenicity in BRCA1 (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-01-18). AlphaMissense: likely benign (0.104); Ultra-rare (popmax 0.0133%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA1 p.Arg7His (c.20G>A)?

BRCA1 p.Arg7His (c.20G>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.Arg7His (c.20G>A) in the general population?

BRCA1 p.Arg7His (c.20G>A) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about BRCA1 p.Arg7His (c.20G>A)?

AlphaMissense predicts likely benign (score 0.104) — an in-silico prediction, not a clinical call.

BRCA1 p.Arg7His

c.20G>A · rs144792613 · VCV184875

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.104 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.104	likely benign
REVEL	0.532	indeterminate
SaProt	LLR -6.08	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	0.052	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 0.0133% Admixed American · 8/59,982 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.000558% 9/1,613,318 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,498
Remaining individualsnot grpmax-eligible	0.0016%	62,444

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.Arg7His
Coding: c.20G>A
MANE Select: NM_007294
dbSNP: rs144792613
Type: single nucleotide variant
Location: chr17:43124077 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 7: a turn

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 pancreatic cancer, susceptibility to, 4 hereditary breast carcinoma Fanconi anemia, complementation group S

Similar variants

BRCA1 p.Arg7= Benign ★★★ same residue
BRCA1 p.Arg7Ser Uncertain significance ★★ ⚠ same residue
BRCA1 p.Arg7Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Arg7Leu Likely benign ★ same residue
BRCA1 p.Arg7fs Pathogenic ★★★ same residue
BRCA1 p.Arg7_Glu10delinsGln 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-arg7his (accessed [today's date]).

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