Is PALB2 p.Arg566Pro (c.1697G>C) pathogenic?

PALB2 p.Arg566Pro (c.1697G>C) is classified Conflicting classifications of pathogenicity in PALB2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-12-01). AlphaMissense: likely benign (0.1699); Very rare (popmax 0.00133%, afr); Associated with breast-ovarian cancer, familial, susceptibility to, 5.

What condition is associated with PALB2 p.Arg566Pro (c.1697G>C)?

PALB2 p.Arg566Pro (c.1697G>C) is associated with breast-ovarian cancer, familial, susceptibility to, 5, Fanconi anemia complementation group N, pancreatic cancer, susceptibility to, 3 (ClinVar).

How common is PALB2 p.Arg566Pro (c.1697G>C) in the general population?

PALB2 p.Arg566Pro (c.1697G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about PALB2 p.Arg566Pro (c.1697G>C)?

AlphaMissense predicts likely benign (score 0.1699) — an in-silico prediction, not a clinical call.

PALB2 p.Arg566Pro

c.1697G>C · rs144617793 · VCV140894

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1699 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

breast-ovarian cancer, familial, susceptibility to, 5

Computational evidence

Protein change
AlphaMissense	0.1699	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -6.95	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.6	GERP -3.3
Regional constraint	o/e 1.00	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	0.197	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 0.00133% African / African-American · 1/74,958 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,611,736 alleles · very rare exomes 6/1,459,534 · genomes 0/152,202 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,958
European (non-Finnish)	0.000424%	235,721

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.Arg566Pro
Coding: c.1697G>C
MANE Select: NM_024675
dbSNP: rs144617793
Type: single nucleotide variant
Location: chr16:23630457 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 566: a UniProt-annotated variant site (risk factor for brovca5); a UniProt-annotated variant site (in fancn; risk factor for brovca5); the 'dna-binding (with the preference d loop > dsdna > ssdna)' region

Full PALB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

breast-ovarian cancer, familial, susceptibility to, 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Fanconi anemia complementation group N pancreatic cancer, susceptibility to, 3 hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

PALB2 p.Arg566Ser Uncertain significance ★★ ⚠ same residue
PALB2 p.Arg566= Benign/Likely benign ★★ same residue
PALB2 p.Arg566Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
PALB2 p.Arg566His Conflicting classifications of pathogenicity ★ ⚠ same residue
PALB2 p.Arg566Leu Uncertain significance ★ ⚠ same residue
PALB2 p.Arg566fs Pathogenic ★★ same residue
PALB2 p.Arg566del Uncertain significance ★★ same residue
PALB2 c.3350+4A>G Likely 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-arg566pro (accessed [today's date]).

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