Is PALB2 p.Pro864Ser (c.2590C>T) pathogenic?

PALB2 p.Pro864Ser (c.2590C>T) is classified Benign/Likely benign in PALB2 (ClinVar, Multiple submitters, 37 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.113); Rare (popmax 0.387%, nfe); Associated with breast-ovarian cancer, familial, susceptibility to, 5.

How common is PALB2 p.Pro864Ser (c.2590C>T) in the general population?

PALB2 p.Pro864Ser (c.2590C>T) is rare (popmax 0.387%, nfe) (gnomAD).

What do computational predictors say about PALB2 p.Pro864Ser (c.2590C>T)?

AlphaMissense predicts likely benign (score 0.113) — an in-silico prediction, not a clinical call.

PALB2 p.Pro864Ser

Q: What condition is associated with PALB2 p.Pro864Ser (c.2590C>T)?

PALB2 p.Pro864Ser (c.2590C>T) is associated with breast-ovarian cancer, familial, susceptibility to, 5, breast carcinoma, breast cancer (ClinVar).

c.2590C>T · rs45568339 · VCV126669

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 37 submitters

AlphaMissense

likely benign

0.113 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.387%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

breast-ovarian cancer, familial, susceptibility to, 5

Computational evidence

Protein change
AlphaMissense	0.113	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -1.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.4	GERP -0.42, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	18.54	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 0.387% European (non-Finnish) · 4,564/1,180,036 alleles

Filtering AF 0.377% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.374%

Overall 0.341% 5,509/1,614,176 alleles · rare exomes 5,084/1,461,876 · genomes 425/152,300 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.22%	82
European (non-Finnish)grpmax	0.387%	259
Remaining individualsnot grpmax-eligible	0.382%	262
Admixed American	0.368%	272
Middle Eastern	0.28%	357
African / African-American	0.0853%	1,173
South Asian	0.0406%	2,462
Finnishnot grpmax-eligible	0.0109%	9,147

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro864Ser
Coding: c.2590C>T
MANE Select: NM_024675
dbSNP: rs45568339
Type: single nucleotide variant
Location: chr16:23626394 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 864: the 'required for interaction with polh and polh dna synthesis stimulation' region; the 'interaction with rad51, brca2 and polh' region; a UniProt-annotated variant site (risk factor for brovca5); a UniProt-annotated variant site (in fancn; risk factor for brovca5); a UniProt-annotated variant site (in)

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 carcinoma breast cancer Fanconi anemia complementation group N pancreatic cancer, susceptibility to, 3 hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

PALB2 p.Pro864His Uncertain significance ★★ ⚠ same residue
PALB2 p.Pro864Leu Uncertain significance ★★ ⚠ same residue
PALB2 p.Pro864= Benign/Likely benign ★★ same residue
PALB2 p.Pro864Thr 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-pro864ser (accessed [today's date]).

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