Is PALB2 p.Pro1008Arg (c.3023C>G) pathogenic?

PALB2 p.Pro1008Arg (c.3023C>G) is classified Uncertain significance in PALB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-08). AlphaMissense: likely benign (0.1729); Absent from gnomAD v4.1; Associated with hereditary breast carcinoma.

What condition is associated with PALB2 p.Pro1008Arg (c.3023C>G)?

PALB2 p.Pro1008Arg (c.3023C>G) is associated with hereditary breast carcinoma (ClinVar).

How common is PALB2 p.Pro1008Arg (c.3023C>G) in the general population?

PALB2 p.Pro1008Arg (c.3023C>G) 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.Pro1008Arg (c.3023C>G)?

AlphaMissense predicts likely benign (score 0.1729) — an in-silico prediction, not a clinical call.

PALB2 p.Pro1008Arg

c.3023C>G · rs1060502736 · VCV2677446

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1729 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
AlphaMissense	0.1729	likely benign
REVEL	0.17	moderately benign-leaning
SaProt	LLR -7.28	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 9.8	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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.Pro1008Arg
Coding: c.3023C>G
MANE Select: NM_024675
dbSNP: rs1060502736
Type: single nucleotide variant
Location: chr16:23621452 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 1008: 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)

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

For Hereditary breast cancer (Orphanet):

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

Similar variants

PALB2 p.Pro1008Leu Uncertain significance ★★ ⚠ same residue
PALB2 p.Pro1008= Benign/Likely benign ★★ same residue
PALB2 p.Pro1008Ser Uncertain significance ★ ⚠ same residue
PALB2 p.Pro1008Thr Uncertain significance ★ ⚠ same residue
PALB2 p.Pro1008His Uncertain significance ★ ⚠ 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-pro1008arg (accessed [today's date]).

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