Is PALB2 p.Ser488Ile (c.1463G>T) pathogenic?

PALB2 p.Ser488Ile (c.1463G>T) is classified Conflicting classifications of pathogenicity in PALB2 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-12-08). AlphaMissense: likely benign (0.1062); Very rare (popmax 0.00801%, afr); Associated with hereditary breast carcinoma.

What condition is associated with PALB2 p.Ser488Ile (c.1463G>T)?

PALB2 p.Ser488Ile (c.1463G>T) is associated with hereditary breast carcinoma, Fanconi anemia complementation group N, pancreatic cancer, susceptibility to, 3 (ClinVar).

How common is PALB2 p.Ser488Ile (c.1463G>T) in the general population?

PALB2 p.Ser488Ile (c.1463G>T) is very rare (popmax 0.00801%, afr) (gnomAD).

How is Hereditary breast cancer inherited?

Typically Autosomal dominant, Multigenic/multifactorial (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PALB2 p.Ser488Ile (c.1463G>T)?

AlphaMissense predicts likely benign (score 0.1062) — an in-silico prediction, not a clinical call.

PALB2 p.Ser488Ile

c.1463G>T · rs767926590 · VCV241530

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1062 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
AlphaMissense	0.1062	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -7.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5	GERP -3.5
Regional constraint	o/e 1.00	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	0.055	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00801% African / African-American · 6/74,920 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.000434% 7/1,614,034 alleles · very rare exomes 3/1,461,866 · genomes 4/152,168 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,487
European (non-Finnish)	8.47e-05%	1,180,020

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.Ser488Ile
Coding: c.1463G>T
MANE Select: NM_024675
dbSNP: rs767926590
Type: single nucleotide variant
Location: chr16:23635083 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 488: the 'disordered' region; a UniProt-annotated variant site (risk factor for brovca5); the 'dna-binding (with the preference d loop > dsdna > ssdna)' region

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

Disease context

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

Also linked: Fanconi anemia complementation group N pancreatic cancer, susceptibility to, 3 hereditary neoplastic syndrome

For Hereditary breast cancer (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adult, Elderly

Similar variants

PALB2 p.Ser488Gly Uncertain significance ★★ ⚠ same residue
PALB2 p.Ser488Arg Uncertain significance ★ ⚠ same residue
PALB2 p.Ser488Cys Uncertain significance ★ ⚠ same residue
PALB2 p.Ser488Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
PALB2 p.Ser488= Benign ★ same residue
PALB2 c.3350+4A>G Likely pathogenic ★★★ same condition
PALB2 p.Arg1117Lys Pathogenic ★★★ ⚠ same condition
PALB2 p.Gln228Ter 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-ser488ile (accessed [today's date]).

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