Is PALB2 p.Ser980= (c.2940C>T) pathogenic?

PALB2 p.Ser980= (c.2940C>T) is classified Conflicting classifications of pathogenicity in PALB2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-12-22). Very rare (popmax 0.00446%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with PALB2 p.Ser980= (c.2940C>T)?

PALB2 p.Ser980= (c.2940C>T) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma, breast-ovarian cancer, familial, susceptibility to, 5 (ClinVar).

How common is PALB2 p.Ser980= (c.2940C>T) in the general population?

PALB2 p.Ser980= (c.2940C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

PALB2 p.Ser980=

c.2940C>T · rs766049739 · VCV415975

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

hereditary neoplastic syndrome

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 5.7	GERP 1.8, phastCons 1
Overall
CADD	10.09	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,886 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000124% 2/1,614,112 alleles · very rare exomes 2/1,461,868 · genomes 0/152,244 · 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.Ser980=
Coding: c.2940C>T
MANE Select: NM_024675
dbSNP: rs766049739
Type: single nucleotide variant
Location: chr16:23623025 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 980: 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 β-strand

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast carcinoma breast-ovarian cancer, familial, susceptibility to, 5

Similar variants

PALB2 p.Ser980Arg Uncertain significance ★ ⚠ same residue
PALB2 p.Ser980fs Pathogenic/Likely 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
PALB2 p.Glu3Ter Pathogenic ★★★ same condition
PALB2 p.Gly853= 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-ser980 (accessed [today's date]).

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