Is BRCA1 p.Pro334His (c.1001C>A) pathogenic?

BRCA1 p.Pro334His (c.1001C>A) is classified Likely benign in BRCA1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-04-14). AlphaMissense: likely benign (0.1463); No allele count reported in gnomAD v4.1 (AN 1,613,774); Associated with hereditary neoplastic syndrome.

What condition is associated with BRCA1 p.Pro334His (c.1001C>A)?

BRCA1 p.Pro334His (c.1001C>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.Pro334His (c.1001C>A) in the general population?

BRCA1 p.Pro334His (c.1001C>A) is no allele count reported in gnomAD v4.1 (AN 1,613,774) (gnomAD).

What do computational predictors say about BRCA1 p.Pro334His (c.1001C>A)?

AlphaMissense predicts likely benign (score 0.1463) — an in-silico prediction, not a clinical call.

BRCA1 p.Pro334His

c.1001C>A · rs41286290 · VCV96893

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1463 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,613,774)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1463	likely benign
REVEL	0.406	indeterminate
SaProt	LLR -6.42	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -0.98, phastCons 0.3
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	18.21	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 1,613,774). 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.Pro334His
Coding: c.1001C>A
MANE Select: NM_007294
dbSNP: rs41286290
Type: single nucleotide variant
Location: chr17:43094530 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 334: the 'disordered' region

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.Pro334Leu Benign ★★★ same residue
BRCA1 p.Pro334Arg Uncertain significance ★★ ⚠ same residue
BRCA1 p.Pro334Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Pro334Ser Uncertain significance ★ ⚠ same residue
BRCA1 p.Pro334Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
BRCA1 p.Pro334= Likely benign ★ 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-pro334his (accessed [today's date]).

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