Is PALB2 p.Phe1016Ser (c.3047T>C) pathogenic?

PALB2 p.Phe1016Ser (c.3047T>C) is classified Uncertain significance in PALB2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-12-28). AlphaMissense: likely pathogenic (0.9159); Absent from gnomAD v4.1; Associated with hereditary breast carcinoma.

What condition is associated with PALB2 p.Phe1016Ser (c.3047T>C)?

PALB2 p.Phe1016Ser (c.3047T>C) is associated with hereditary breast carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is PALB2 p.Phe1016Ser (c.3047T>C) in the general population?

PALB2 p.Phe1016Ser (c.3047T>C) is absent from gnomAD v4.1 (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.Phe1016Ser (c.3047T>C)?

AlphaMissense predicts likely pathogenic (score 0.9159) — an in-silico prediction, not a clinical call.

PALB2 p.Phe1016Ser

c.3047T>C · rs879254154 · VCV420578

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9159 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
AlphaMissense	0.9159	likely pathogenic · top 2% in PALB2
REVEL	0.563	indeterminate
SaProt	LLR -13.09	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PALB2
Protein: p.Phe1016Ser
Coding: c.3047T>C
MANE Select: NM_024675
dbSNP: rs879254154
Type: single nucleotide variant
Location: chr16:23621428 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 1016: 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 breast carcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Hereditary breast cancer (Orphanet):

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

Similar variants

PALB2 p.Phe1016Cys Uncertain significance ★★ ⚠ same residue
PALB2 p.Phe1016Leu Uncertain significance ★★ ⚠ same residue
PALB2 p.Phe1016= Likely benign ★ same residue
PALB2 p.Phe1016fs 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

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-phe1016ser (accessed [today's date]).

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