Is PALB2 p.Phe776fs (c.2325dup) pathogenic?

PALB2 p.Phe776fs (c.2325dup) is classified Pathogenic in PALB2 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-01-19). Very rare (popmax 0.0022%, nfe); Associated with PALB2-related disorder.

What condition is associated with PALB2 p.Phe776fs (c.2325dup)?

PALB2 p.Phe776fs (c.2325dup) is associated with PALB2-related disorder, hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is PALB2 p.Phe776fs (c.2325dup) in the general population?

PALB2 p.Phe776fs (c.2325dup) is very rare (popmax 0.0022%, nfe) (gnomAD).

PALB2 p.Phe776fs

c.2325dup · rs876659997 · VCV232803

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0022%, nfe)

Conditions

PALB2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 5 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.33	GERP 0.62

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% European (non-Finnish) · 26/1,180,028 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00161% 26/1,614,172 alleles · very rare exomes 26/1,461,892 · genomes 0/152,280 · joint denominator

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.Phe776fs
Coding: c.2325dup
MANE Select: NM_024675
dbSNP: rs876659997
Type: Duplication
Location: chr16:23629828 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 776: 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

PALB2-related disorder

Also linked: hereditary neoplastic syndrome hereditary breast carcinoma PALB2-related cancer predisposition

Similar variants

PALB2 p.Phe776= Benign/Likely benign ★★ same residue
PALB2 p.Phe776Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
PALB2 p.Ala995fs Pathogenic/Likely pathogenic ★★ same condition
PALB2 p.Arg153fs Pathogenic ★★ same condition
PALB2 p.Arg464fs Pathogenic ★★ same condition
PALB2 p.Asn280fs Pathogenic ★★ same condition
PALB2 p.Asn330Ter Pathogenic ★★ same condition
PALB2 p.Asn540fs 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-phe776fs (accessed [today's date]).

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