Is PALB2 p.Lys449= (c.1347A>G) pathogenic?

PALB2 p.Lys449= (c.1347A>G) is classified Conflicting classifications of pathogenicity in PALB2 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-18). Very rare (popmax 0.00305%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with PALB2 p.Lys449= (c.1347A>G)?

PALB2 p.Lys449= (c.1347A>G) is associated with hereditary neoplastic syndrome, pancreatic cancer, susceptibility to, 3, hereditary breast carcinoma (ClinVar).

How common is PALB2 p.Lys449= (c.1347A>G) in the general population?

PALB2 p.Lys449= (c.1347A>G) is very rare (popmax 0.00305%, nfe) (gnomAD).

PALB2 p.Lys449=

c.1347A>G · rs587780205 · VCV128118

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00305%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.71	GERP 1.7, phastCons 0.48
Overall
CADD	5.879	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00305% European (non-Finnish) · 36/1,180,030 alleles

Filtering AF 0.00223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.00246% 36/1,461,830 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.Lys449=
Coding: c.1347A>G
MANE Select: NM_024675
dbSNP: rs587780205
Type: single nucleotide variant
Location: chr16:23635199 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 449: the 'disordered' region; a UniProt-annotated variant site (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

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

Also linked: pancreatic cancer, susceptibility to, 3 hereditary breast carcinoma

Similar variants

PALB2 p.Lys449Ile Uncertain significance ★★ ⚠ same residue
PALB2 p.Lys449Thr 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
PALB2 p.Gln692Ter Likely pathogenic ★★★ same condition
PALB2 p.Glu3Ter Pathogenic ★★★ same condition
PALB2 p.Gly853= 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-lys449 (accessed [today's date]).

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