Is PALB2 p.Pro1097Ser (c.3289C>T) pathogenic?

PALB2 p.Pro1097Ser (c.3289C>T) is classified Uncertain significance in PALB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-06). AlphaMissense: likely pathogenic (0.8961); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary breast carcinoma.

What condition is associated with PALB2 p.Pro1097Ser (c.3289C>T)?

PALB2 p.Pro1097Ser (c.3289C>T) is associated with hereditary breast carcinoma (ClinVar).

How common is PALB2 p.Pro1097Ser (c.3289C>T) in the general population?

PALB2 p.Pro1097Ser (c.3289C>T) is very rare (popmax 8.47e-05%, nfe) (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 PALB2 p.Pro1097Ser (c.3289C>T)?

AlphaMissense predicts likely pathogenic (score 0.8961) — an in-silico prediction, not a clinical call.

PALB2 p.Pro1097Ser

c.3289C>T · rs1966508272 · VCV1005193

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8961 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
AlphaMissense	0.8961	likely pathogenic · top 3% in PALB2
REVEL	0.458	indeterminate
SaProt	LLR -8.13	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	23.9	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 8.47e-05% European (non-Finnish) · 1/1,180,016 alleles

Overall 6.84e-05% 1/1,461,880 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: PALB2
Protein: p.Pro1097Ser
Coding: c.3289C>T
MANE Select: NM_024675
dbSNP: rs1966508272
Type: single nucleotide variant
Location: chr16:23607925 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 1097: a turn; the 'required for interaction with polh and polh dna synthesis stimulation' region; the 'interaction with rad51, brca2 and polh' region; a UniProt-annotated variant site (risk factor for brovca5); a UniProt-annotated variant site (in fancn; risk factor for brovca5); a UniProt-annotated variant site (risk factor for brovca5; risk factor for pnca3)

Full PALB2 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

For Hereditary breast cancer (Orphanet):

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

Similar variants

PALB2 p.Pro1097Arg Uncertain significance ★★ ⚠ same residue
PALB2 p.Pro1097Leu Uncertain significance ★★ ⚠ same residue
PALB2 p.Pro1097Thr Uncertain significance ★★ ⚠ same residue
PALB2 p.Pro1097= Benign/Likely benign ★★ same residue
PALB2 p.Pro1097His Uncertain significance ★ ⚠ same residue
PALB2 c.3350+4A>G Likely pathogenic ★★★ same condition
PALB2 p.Arg1117Lys Pathogenic ★★★ ⚠ same condition
PALB2 p.Gln228Ter 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/palb2-p-pro1097ser (accessed [today's date]).

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