Is BRCA1 p.Ser1722Phe (c.5165C>T) pathogenic?

BRCA1 p.Ser1722Phe (c.5165C>T) is classified Conflicting classifications of pathogenicity in BRCA1 (ClinVar, Conflicting submitters, 21 submitters; last evaluated 2025-12-05). AlphaMissense: likely pathogenic (0.9504); Very rare (popmax 0.00167%, amr); Associated with hereditary breast carcinoma.

What condition is associated with BRCA1 p.Ser1722Phe (c.5165C>T)?

BRCA1 p.Ser1722Phe (c.5165C>T) is associated with hereditary breast carcinoma, hereditary breast ovarian cancer syndrome, breast cancer (ClinVar).

How common is BRCA1 p.Ser1722Phe (c.5165C>T) in the general population?

BRCA1 p.Ser1722Phe (c.5165C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Hereditary breast cancer inherited?

Typically Autosomal dominant, Multigenic/multifactorial (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about BRCA1 p.Ser1722Phe (c.5165C>T)?

AlphaMissense predicts likely pathogenic (score 0.9504) — an in-silico prediction, not a clinical call.

BRCA1 p.Ser1722Phe

c.5165C>T · rs80357104 · VCV55441

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 21 submitters

AlphaMissense

likely pathogenic

0.9504 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
AlphaMissense	0.9504	likely pathogenic · top 2% in BRCA1
REVEL	0.756	pathogenic-leaning
SaProt	LLR -16.77	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 7.5	GERP 2.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 78 kb · p 4.8e-05 · regional, not allelic
Overall
CADD	24.4	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 0.00167% Admixed American · 1/59,994 alleles

Overall 6.85e-05% 1/1,459,212 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.Ser1722Phe
Coding: c.5165C>T
MANE Select: NM_007294
dbSNP: rs80357104
Type: single nucleotide variant
Location: chr17:43063361 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 41.99 · 33 PDB
Residue 1722: the brct 1 domain; a UniProt-annotated variant site (in fancs); an α-helix

Full BRCA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: hereditary breast ovarian cancer syndrome breast cancer breast-ovarian cancer, familial, susceptibility to, 1 pancreatic cancer, susceptibility to, 4 hereditary neoplastic syndrome Fanconi anemia, complementation group S

For Hereditary breast cancer (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adult, Elderly

Similar variants

BRCA1 p.Ser1722Tyr Uncertain significance ★★★ ⚠ same residue
BRCA1 p.Ser1722Pro Likely pathogenic ★★ same residue
BRCA1 p.Ser1722Cys Uncertain significance ★★ ⚠ same residue
BRCA1 p.Ser1722fs Pathogenic ★★★ same residue
BRCA1 p.Ser1722_Ile1723insTer Pathogenic ★★ 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

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-ser1722phe (accessed [today's date]).

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