Is PALB2 p.Leu499= (c.1497G>A) pathogenic?

PALB2 p.Leu499= (c.1497G>A) is classified Benign/Likely benign in PALB2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-04-09). Very rare (popmax 0.00169%, nfe); Associated with Fanconi anemia complementation group N.

What condition is associated with PALB2 p.Leu499= (c.1497G>A)?

PALB2 p.Leu499= (c.1497G>A) is associated with Fanconi anemia complementation group N, pancreatic cancer, susceptibility to, 3, hereditary neoplastic syndrome (ClinVar).

How common is PALB2 p.Leu499= (c.1497G>A) in the general population?

PALB2 p.Leu499= (c.1497G>A) is very rare (popmax 0.00169%, nfe) (gnomAD).

PALB2 p.Leu499=

c.1497G>A · rs748315431 · VCV391674

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00169%, nfe)

Conditions

Fanconi anemia complementation group N

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 0.42	GERP -3.5
Overall
CADD	1.802	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00169% European (non-Finnish) · 20/1,180,032 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.0013% 21/1,614,118 alleles · very rare exomes 21/1,461,888 · genomes 0/152,230 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00169%	59,002
Remaining individualsnot grpmax-eligible	0.0016%	62,508

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.Leu499=
Coding: c.1497G>A
MANE Select: NM_024675
dbSNP: rs748315431
Type: single nucleotide variant
Location: chr16:23635049 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 499: 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

Fanconi anemia complementation group N — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pancreatic cancer, susceptibility to, 3 hereditary neoplastic syndrome hereditary breast carcinoma breast-ovarian cancer, familial, susceptibility to, 5

Similar variants

PALB2 p.Leu499Ter Pathogenic/Likely pathogenic ★★ same residue
PALB2 p.Leu499Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
PALB2 p.Leu499Ser Uncertain significance ★ ⚠ same residue
PALB2 p.Leu499Val 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

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-leu499 (accessed [today's date]).

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