Is PALB2 p.Cys396= (c.1188C>T) pathogenic?

PALB2 p.Cys396= (c.1188C>T) is classified Benign/Likely benign in PALB2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-12-10). Very rare (popmax 0.00636%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with PALB2 p.Cys396= (c.1188C>T)?

PALB2 p.Cys396= (c.1188C>T) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is PALB2 p.Cys396= (c.1188C>T) in the general population?

PALB2 p.Cys396= (c.1188C>T) is very rare (popmax 0.00636%, nfe) (gnomAD).

PALB2 p.Cys396=

c.1188C>T · rs587780817 · VCV136126

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00636%, 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 0.77	GERP -3.5, phastCons 1
Overall
CADD	3.679	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00636% European (non-Finnish) · 75/1,180,030 alleles

Filtering AF 0.00519% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00474%

Overall 0.00483% 78/1,613,852 alleles · very rare exomes 76/1,461,642 · genomes 2/152,210 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00636%	15,734
African / African-American	0.00267%	37,469
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Cys396=
Coding: c.1188C>T
MANE Select: NM_024675
dbSNP: rs587780817
Type: single nucleotide variant
Location: chr16:23635358 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 396: 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 carcinoma

Similar variants

PALB2 p.Cys396Ter Pathogenic ★★ same residue
PALB2 p.Cys396Arg Uncertain significance ★★ ⚠ same residue
PALB2 p.Cys396Trp Uncertain significance ★★ ⚠ same residue
PALB2 p.Cys396Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
PALB2 p.Cys396fs Pathogenic ★★ 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-cys396 (accessed [today's date]).

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