Is PALB2 p.Pro782Ser (c.2344C>T) pathogenic?

PALB2 p.Pro782Ser (c.2344C>T) is classified Conflicting classifications of pathogenicity in PALB2 (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2025-08-28). AlphaMissense: likely benign (0.0848); Very rare (popmax 0.00667%, afr); Associated with hereditary breast carcinoma.

What condition is associated with PALB2 p.Pro782Ser (c.2344C>T)?

PALB2 p.Pro782Ser (c.2344C>T) is associated with hereditary breast carcinoma, breast cancer, Fanconi anemia complementation group N (ClinVar).

How common is PALB2 p.Pro782Ser (c.2344C>T) in the general population?

PALB2 p.Pro782Ser (c.2344C>T) is very rare (popmax 0.00667%, afr) (gnomAD).

How is Hereditary breast cancer inherited?

Typically Autosomal dominant, Multigenic/multifactorial (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PALB2 p.Pro782Ser (c.2344C>T)?

AlphaMissense predicts likely benign (score 0.0848) — an in-silico prediction, not a clinical call.

PALB2 p.Pro782Ser

c.2344C>T · rs786203296 · VCV186885

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.0848 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
AlphaMissense	0.0848	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -5.52	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.27	GERP -3.5
Regional constraint	o/e 1.00	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	0.417	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% African / African-American · 5/74,922 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.000496% 8/1,614,032 alleles · very rare exomes 6/1,461,880 · genomes 2/152,152 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,984
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.000169%	590,016

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.Pro782Ser
Coding: c.2344C>T
MANE Select: NM_024675
dbSNP: rs786203296
Type: single nucleotide variant
Location: chr16:23629810 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 782: the 'disordered' region; the 'required for interaction with polh and polh dna synthesis stimulation' region; a UniProt-annotated variant site (risk factor for brovca5); a UniProt-annotated variant site (in fancn; risk factor for brovca5)

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

Disease context

hereditary breast carcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: breast cancer Fanconi anemia complementation group N pancreatic cancer, susceptibility to, 3 hereditary neoplastic syndrome

For Hereditary breast cancer (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adult, Elderly

Similar variants

PALB2 p.Pro782Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
PALB2 p.Pro782Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
PALB2 p.Pro782= Likely benign ★ 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
PALB2 p.Glu3Ter 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-pro782ser (accessed [today's date]).

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