Is PALB2 p.Ala519= (c.1557C>T) pathogenic?

PALB2 p.Ala519= (c.1557C>T) is classified Benign/Likely benign in PALB2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-20). Very rare (popmax 0.00167%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with PALB2 p.Ala519= (c.1557C>T)?

PALB2 p.Ala519= (c.1557C>T) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is PALB2 p.Ala519= (c.1557C>T) in the general population?

PALB2 p.Ala519= (c.1557C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

PALB2 p.Ala519=

c.1557C>T · rs752349785 · VCV402293

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

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 0.39	GERP -1.8
Overall
CADD	1.032	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,000 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00031% 5/1,614,080 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,000
Remaining individualsnot grpmax-eligible	0.0016%	62,490
South Asian	0.0011%	91,080
European (non-Finnish)	0.000169%	590,026

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.Ala519=
Coding: c.1557C>T
MANE Select: NM_024675
dbSNP: rs752349785
Type: single nucleotide variant
Location: chr16:23634989 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 519: 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: hereditary breast carcinoma

Similar variants

PALB2 p.Ala519Gly Uncertain significance ★★ ⚠ same residue
PALB2 p.Ala519Pro Uncertain significance ★★ ⚠ same residue
PALB2 p.Ala519Val Uncertain significance ★★ ⚠ same residue
PALB2 p.Ala519Asp Conflicting classifications of pathogenicity ★ ⚠ same residue
PALB2 p.Ala519Ser Uncertain significance ★ ⚠ same residue
PALB2 p.Ala519Thr Uncertain significance ★ ⚠ 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-ala519 (accessed [today's date]).

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