Is PALB2 p.Pro358Ser (c.1072C>T) pathogenic?

PALB2 p.Pro358Ser (c.1072C>T) is classified Conflicting classifications of pathogenicity in PALB2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-26). AlphaMissense: likely benign (0.0762); Very rare (popmax 0.000763%, nfe); Associated with Fanconi anemia complementation group N.

What condition is associated with PALB2 p.Pro358Ser (c.1072C>T)?

PALB2 p.Pro358Ser (c.1072C>T) is associated with Fanconi anemia complementation group N, pancreatic cancer, susceptibility to, 3, hereditary neoplastic syndrome (ClinVar).

How common is PALB2 p.Pro358Ser (c.1072C>T) in the general population?

PALB2 p.Pro358Ser (c.1072C>T) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about PALB2 p.Pro358Ser (c.1072C>T)?

AlphaMissense predicts likely benign (score 0.0762) — an in-silico prediction, not a clinical call.

PALB2 p.Pro358Ser

c.1072C>T · rs876660876 · VCV234140

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0762 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Fanconi anemia complementation group N

Computational evidence

Protein change
AlphaMissense	0.0762	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	LLR -4.94	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 0.81	GERP -1.6, phastCons 0.96
Regional constraint	o/e 1.00	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	1.748	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 0.000763% European (non-Finnish) · 9/1,180,014 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000616% 9/1,461,822 alleles · very rare

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.Pro358Ser
Coding: c.1072C>T
MANE Select: NM_024675
dbSNP: rs876660876
Type: single nucleotide variant
Location: chr16:23635474 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 358: the 'disordered' 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

Fanconi anemia complementation group N — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pancreatic cancer, susceptibility to, 3 hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

PALB2 p.Pro358His Uncertain significance ★★ ⚠ same residue
PALB2 p.Pro358Ala Uncertain significance ★ ⚠ same residue
PALB2 p.Pro358Arg Uncertain significance ★ ⚠ same residue
PALB2 p.Pro358Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
PALB2 p.Pro358= Likely benign ★ same residue
PALB2 p.Pro358fs Pathogenic ★★ same residue
PALB2 p.Pro358Phe Uncertain significance ★ same residue
PALB2 c.3350+4A>G 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-pro358ser (accessed [today's date]).

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