Is PALB2 p.Ser689= (c.2067G>A) pathogenic?

PALB2 p.Ser689= (c.2067G>A) is classified Conflicting classifications of pathogenicity in PALB2 (ClinVar, Conflicting submitters, 16 submitters; last evaluated 2026-01-31). Ultra-rare (popmax 0.0557%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with PALB2 p.Ser689= (c.2067G>A)?

PALB2 p.Ser689= (c.2067G>A) is associated with hereditary neoplastic syndrome, colon carcinoma, Fanconi anemia complementation group N (ClinVar).

How common is PALB2 p.Ser689= (c.2067G>A) in the general population?

PALB2 p.Ser689= (c.2067G>A) is ultra-rare (popmax 0.0557%, eas) (gnomAD).

PALB2 p.Ser689=

c.2067G>A · rs371149159 · VCV185889

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 16 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0557%, 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 -2	GERP -3.7
Overall
CADD	1.02	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0557% East Asian · 25/44,904 alleles

Filtering AF 0.0386% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.033%

Overall 0.00434% 70/1,613,996 alleles · ultra-rare exomes 64/1,461,886 · genomes 6/152,110 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0557%	1,796
Remaining individualsnot grpmax-eligible	0.008%	12,497
South Asian	0.00329%	30,359
European (non-Finnish)	0.00297%	33,715
Admixed American	0.00167%	59,992
African / African-American	0.00134%	74,902

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.Ser689=
Coding: c.2067G>A
MANE Select: NM_024675
dbSNP: rs371149159
Type: single nucleotide variant
Location: chr16:23630087 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 689: the 'disordered' 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

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

Also linked: colon carcinoma Fanconi anemia complementation group N hereditary breast carcinoma

Similar variants

PALB2 p.Ser689Ter Pathogenic ★★ same residue
PALB2 p.Ser689Ala Uncertain significance ★★ ⚠ same residue
PALB2 p.Ser689Leu Conflicting classifications of pathogenicity ★ ⚠ 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

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-ser689 (accessed [today's date]).

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