Is PALB2 p.Ser256= (c.768C>T) pathogenic?

PALB2 p.Ser256= (c.768C>T) is classified Benign/Likely benign in PALB2 (ClinVar, Multiple submitters, 20 submitters; last evaluated 2026-02-02). Ultra-rare (popmax 0.0527%, sas); Associated with breast-ovarian cancer, familial, susceptibility to, 5.

What condition is associated with PALB2 p.Ser256= (c.768C>T)?

PALB2 p.Ser256= (c.768C>T) is associated with breast-ovarian cancer, familial, susceptibility to, 5, breast cancer, hereditary neoplastic syndrome (ClinVar).

How common is PALB2 p.Ser256= (c.768C>T) in the general population?

PALB2 p.Ser256= (c.768C>T) is ultra-rare (popmax 0.0527%, sas) (gnomAD).

PALB2 p.Ser256=

c.768C>T · rs45487491 · VCV184338

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 20 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0527%, sas)

Conditions

breast-ovarian cancer, familial, susceptibility to, 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.5	GERP -2.9, phastCons 0.002
Overall
CADD	7.152	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0527% South Asian · 48/91,076 alleles

Filtering AF 0.0408% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0366%

Overall 0.00812% 131/1,614,002 alleles · ultra-rare exomes 121/1,461,792 · genomes 10/152,210 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0527%	1,897
Middle Eastern	0.0495%	2,021
East Asian	0.0357%	2,804
Remaining individualsnot grpmax-eligible	0.0128%	7,812
African / African-American	0.00667%	15,002
European (non-Finnish)	0.00424%	23,599
Admixed American	0.00167%	60,004

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.Ser256=
Coding: c.768C>T
MANE Select: NM_024675
dbSNP: rs45487491
Type: single nucleotide variant
Location: chr16:23635778 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 256: the 'disordered' region; the 'dna-binding (with the preference d loop > dsdna > ssdna)' region; the 'interaction with brca1' region

Full PALB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

breast-ovarian cancer, familial, susceptibility to, 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: breast cancer hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

PALB2 p.Ser256Gly Uncertain significance ★★ ⚠ same residue
PALB2 p.Ser256Arg Uncertain significance ★ ⚠ same residue
PALB2 p.Ser256Asn Uncertain significance ★ ⚠ same residue
PALB2 p.Ser256Thr 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-ser256 (accessed [today's date]).

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