Is BRCA1 p.Pro34Arg (c.101C>G) pathogenic?

BRCA1 p.Pro34Arg (c.101C>G) is classified Likely pathogenic in BRCA1 (ClinVar, Single submitter, 2 submitters; last evaluated 2020-07-27). AlphaMissense: likely pathogenic (0.9886); Very rare (popmax 0.00017%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA1 p.Pro34Arg (c.101C>G)?

BRCA1 p.Pro34Arg (c.101C>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is BRCA1 p.Pro34Arg (c.101C>G) in the general population?

BRCA1 p.Pro34Arg (c.101C>G) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about BRCA1 p.Pro34Arg (c.101C>G)?

AlphaMissense predicts likely pathogenic (score 0.9886) — an in-silico prediction, not a clinical call.

BRCA1 p.Pro34Arg

c.101C>G · rs786203319 · VCV867486

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9886 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9886	likely pathogenic ✓ concordant with ClinVar · top 1% in BRCA1
REVEL	0.85	moderately pathogenic-leaning
SaProt	LLR -16.92	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	27.5	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

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,798 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,432 alleles · very rare

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.Pro34Arg
Coding: c.101C>G
MANE Select: NM_007294
dbSNP: rs786203319
Type: single nucleotide variant
Location: chr17:43115759 (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 neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BRCA1 p.Pro34Leu Likely pathogenic ★★★ same residue
BRCA1 p.Pro34Ser Likely pathogenic ★★★ same residue
BRCA1 p.Pro34Thr Uncertain significance ★ ⚠ same residue
BRCA1 p.Pro34= Likely benign ★ 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-pro34arg (accessed [today's date]).

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