Is PALB2 p.Ser10Arg (c.30C>G) pathogenic?

PALB2 p.Ser10Arg (c.30C>G) is classified Conflicting classifications of pathogenicity in PALB2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-05). AlphaMissense: likely pathogenic (0.8234); Very rare (popmax 8.48e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with PALB2 p.Ser10Arg (c.30C>G)?

PALB2 p.Ser10Arg (c.30C>G) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is PALB2 p.Ser10Arg (c.30C>G) in the general population?

PALB2 p.Ser10Arg (c.30C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about PALB2 p.Ser10Arg (c.30C>G)?

AlphaMissense predicts likely pathogenic (score 0.8234) — an in-silico prediction, not a clinical call.

PALB2 p.Ser10Arg

c.30C>G · rs758500749 · VCV1497470

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8234 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.8234	likely pathogenic · top 4% in PALB2
REVEL	0.171	moderately benign-leaning
SaProt	LLR -10.64	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	Δ0.98	donor gain · deltas
Pangolin	Δ0.73	gain · loss 0.29 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5	GERP 0.71, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	34.0	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 8.48e-05% European (non-Finnish) · 1/1,179,872 alleles

Overall 6.84e-05% 1/1,461,246 alleles · very rare

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.Ser10Arg
Coding: c.30C>G
MANE Select: NM_024675
dbSNP: rs758500749
Type: single nucleotide variant
Location: chr16:23641128 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 10: the 'interaction with rad51' region; the 'required for its oligomerization and is important for its focal concentration at dna damage sites' region; the 'dna-binding (with the preference d loop > dsdna > ssdna)' region; the 'interaction with brca1' region

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

Similar variants

PALB2 p.Ser10Ile Uncertain significance ★★ ⚠ same residue
PALB2 p.Ser10= Benign/Likely benign ★★ same residue
PALB2 p.Ser10Asn Uncertain significance ★ ⚠ same residue
PALB2 p.Ser10Cys Uncertain significance ★ ⚠ same residue
PALB2 p.Ser10Gly Uncertain significance ★ ⚠ same residue
PALB2 p.Ser10Thr Uncertain significance ★ ⚠ same residue
PALB2 c.3350+4A>G Likely pathogenic ★★★ same condition
PALB2 p.Arg1117Lys 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-ser10arg (accessed [today's date]).

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