Is PALB2 p.Lys681Arg (c.2042A>G) pathogenic?

PALB2 p.Lys681Arg (c.2042A>G) is classified Uncertain significance in PALB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-02). AlphaMissense: likely benign (0.1012); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with PALB2 p.Lys681Arg (c.2042A>G)?

PALB2 p.Lys681Arg (c.2042A>G) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is PALB2 p.Lys681Arg (c.2042A>G) in the general population?

PALB2 p.Lys681Arg (c.2042A>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about PALB2 p.Lys681Arg (c.2042A>G)?

AlphaMissense predicts likely benign (score 0.1012) — an in-silico prediction, not a clinical call.

PALB2 p.Lys681Arg

c.2042A>G · rs1555460514 · VCV2002808

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1012 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1012	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -6.54	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 1.2	GERP -0.36, phastCons 0.021
Regional constraint	o/e 1.00	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	11.36	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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) · 1/1,180,042 alleles

Overall 6.2e-05% 1/1,614,188 alleles · very rare exomes 1/1,461,878 · genomes 0/152,310 · joint denominator

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.Lys681Arg
Coding: c.2042A>G
MANE Select: NM_024675
dbSNP: rs1555460514
Type: single nucleotide variant
Location: chr16:23630112 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 681: the 'disordered' region; a UniProt-annotated variant site (risk factor for brovca5); a UniProt-annotated variant site (in fancn; risk factor for brovca5)

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: hereditary breast carcinoma

Similar variants

PALB2 p.Lys681= Benign/Likely benign ★★ same residue
PALB2 p.Lys681Ter Pathogenic ★ same residue
PALB2 p.Lys681Gln Uncertain significance ★ ⚠ same residue
PALB2 p.Lys681Glu Uncertain significance ★ ⚠ same residue
PALB2 p.Lys681Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
PALB2 p.Lys681fs Pathogenic ★ same residue
PALB2 c.3350+4A>G Likely pathogenic ★★★ same condition
PALB2 p.Arg1117Lys 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-lys681arg (accessed [today's date]).

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