Is PALB2 p.Pro104= (c.312T>C) pathogenic?

PALB2 p.Pro104= (c.312T>C) is classified Benign/Likely benign in PALB2 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-01-11). Very rare (popmax 0.00576%, nfe); Associated with Breast and/or ovarian cancer.

What condition is associated with PALB2 p.Pro104= (c.312T>C)?

PALB2 p.Pro104= (c.312T>C) is associated with Breast and/or ovarian cancer, hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is PALB2 p.Pro104= (c.312T>C) in the general population?

PALB2 p.Pro104= (c.312T>C) is very rare (popmax 0.00576%, nfe) (gnomAD).

PALB2 p.Pro104=

c.312T>C · rs749203259 · VCV184298

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00576%, nfe)

Conditions

Breast and/or ovarian cancer

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.4	GERP -3.7
Overall
CADD	2.123	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00576% European (non-Finnish) · 68/1,179,968 alleles

Filtering AF 0.00462% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00423%

Overall 0.00421% 68/1,613,696 alleles · very rare exomes 66/1,461,648 · genomes 2/152,048 · 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.Pro104=
Coding: c.312T>C
MANE Select: NM_024675
dbSNP: rs749203259
Type: single nucleotide variant
Location: chr16:23636234 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 104: the 'interaction with rad51' region; the 'required for its oligomerization and is important for its focal concentration at dna damage sites' region; the 'disordered' region; the 'dna-binding (with the preference d loop > dsdna > ssdna)' region; the 'interaction with brca1' region

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

Disease context

Breast and/or ovarian cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

PALB2 p.Pro104Ser Uncertain significance ★★ ⚠ same residue
PALB2 p.Pro104Ala Uncertain significance ★ ⚠ same residue
PALB2 p.Pro104Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
PALB2 p.Pro104fs Pathogenic ★★ 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-pro104 (accessed [today's date]).

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