Is PALB2 p.Ala427= (c.1281T>C) pathogenic?

PALB2 p.Ala427= (c.1281T>C) is classified Conflicting classifications of pathogenicity in PALB2 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-02-01). Ultra-rare (popmax 0.0693%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with PALB2 p.Ala427= (c.1281T>C)?

PALB2 p.Ala427= (c.1281T>C) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, Fanconi anemia complementation group N (ClinVar).

How common is PALB2 p.Ala427= (c.1281T>C) in the general population?

PALB2 p.Ala427= (c.1281T>C) is ultra-rare (popmax 0.0693%, afr) (gnomAD).

PALB2 p.Ala427=

c.1281T>C · rs138697796 · VCV138577

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0693%, afr)

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 4.8	GERP 1.7, phastCons 1
Overall
CADD	11.22	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0693% African / African-American · 52/75,056 alleles

Filtering AF 0.0542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0489%

Overall 0.00366% 59/1,614,176 alleles · ultra-rare exomes 32/1,461,842 · genomes 27/152,334 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0693%	1,443
Remaining individualsnot grpmax-eligible	0.008%	12,502
Admixed American	0.00167%	60,018
South Asian	0.0011%	91,088

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.Ala427=
Coding: c.1281T>C
MANE Select: NM_024675
dbSNP: rs138697796
Type: single nucleotide variant
Location: chr16:23635265 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 427: the 'cham (chromatin-association motif); required for chromatin association, mediates nucleosome association' 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 ovarian cancer syndrome Fanconi anemia complementation group N pancreatic cancer, susceptibility to, 3 hereditary breast carcinoma

Similar variants

PALB2 p.Ala427Val Uncertain significance ★★ ⚠ same residue
PALB2 p.Ala427Gly Uncertain significance ★ ⚠ same residue
PALB2 p.Ala427Pro Uncertain significance ★ ⚠ same residue
PALB2 p.Ala427fs Pathogenic ★ same residue
PALB2 p.Ala427Thr 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

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-ala427 (accessed [today's date]).

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