Is PALB2 p.Ser804fs (c.2411_2412del) pathogenic?

PALB2 p.Ser804fs (c.24112412del) is classified Pathogenic in PALB2 (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-01-05). Very rare (popmax 0.00833%, amr); Associated with PALB2-related disorder.

What condition is associated with PALB2 p.Ser804fs (c.2411_2412del)?

PALB2 p.Ser804fs (c.2411_2412del) is associated with PALB2-related disorder, hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is PALB2 p.Ser804fs (c.2411_2412del) in the general population?

PALB2 p.Ser804fs (c.2411_2412del) is very rare (popmax 0.00833%, amr) (gnomAD).

PALB2 p.Ser804fs

c.2411_2412del · rs747148023 · VCV231143

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

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 0.22	GERP 0.57
Overall
CADD	22.2	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00833% Admixed American · 5/60,000 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000434% 7/1,614,064 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,000
African / African-American	0.00267%	37,463

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.Ser804fs
Coding: c.2411_2412del
MANE Select: NM_024675
dbSNP: rs747148023
Type: Microsatellite
Location: chr16:23629742 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 804: 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 breast ovarian cancer syndrome hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

PALB2 p.Ser804Cys Uncertain significance ★★ ⚠ same residue
PALB2 p.Ser804_Val805insAspSer Uncertain significance ★ same residue
PALB2 p.Ser804Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
PALB2 p.Ser804Pro Uncertain significance ★ ⚠ same residue
PALB2 p.Ser804= Benign ★ same residue
PALB2 p.Asn930fs Pathogenic ★★★ same condition
PALB2 p.Arg975fs Pathogenic ★★ same condition
PALB2 p.Asp161fs 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-ser804fs (accessed [today's date]).

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