Is PALB2 p.Arg37Ser (c.109C>A) pathogenic?

PALB2 p.Arg37Ser (c.109C>A) is classified Uncertain significance in PALB2 (ClinVar, Expert panel, 14 submitters; last evaluated 2023-04-05). AlphaMissense: likely pathogenic (0.9577); Ultra-rare (popmax 0.016%, afr); Associated with PALB2-related cancer predisposition.

What condition is associated with PALB2 p.Arg37Ser (c.109C>A)?

PALB2 p.Arg37Ser (c.109C>A) is associated with PALB2-related cancer predisposition, hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is PALB2 p.Arg37Ser (c.109C>A) in the general population?

PALB2 p.Arg37Ser (c.109C>A) is ultra-rare (popmax 0.016%, afr) (gnomAD).

What do computational predictors say about PALB2 p.Arg37Ser (c.109C>A)?

AlphaMissense predicts likely pathogenic (score 0.9577) — an in-silico prediction, not a clinical call.

PALB2 p.Arg37Ser

c.109C>A · rs200048921 · VCV185108

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 14 submitters

AlphaMissense

likely pathogenic

0.9577 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PALB2-related cancer predisposition

ClinGen expert panel — Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

Uncertain Significance for PALB2-related cancer predisposition. Applied ACMG criteria (verbatim):

BP1

Curation rationale (ClinGen, verbatim)

The c.109C>A variant in PALB2 is a missense variant predicted to cause substitution of arginine by serine at amino acid 37 (p.Arg37Ser). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00012 in the African population (PM2_Supporting, BS1, and BA1 are not met). This variant is functional in multiple different protein assays (PMID: 31636395); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (BP1)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9577	likely pathogenic · top 1% in PALB2
REVEL	0.195	benign-leaning
SaProt	LLR -7.36	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	28.8	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 0.016% African / African-American · 12/74,864 alleles

Filtering AF 0.00922% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00722%

Overall 0.000992% 16/1,612,736 alleles · ultra-rare exomes 8/1,460,624 · genomes 8/152,112 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,239
Admixed American	0.00333%	29,992
Remaining individualsnot grpmax-eligible	0.0032%	31,220

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.Arg37Ser
Coding: c.109C>A
MANE Select: NM_024675
dbSNP: rs200048921
Type: single nucleotide variant
Location: chr16:23637952 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 37: the 'interaction with rad51' region; the 'required for its oligomerization and is important for its focal concentration at dna damage sites' region; a UniProt-annotated variant site (decreases double-stranded dna break-initiated homologous recombination); an α-helix; 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

Also linked: hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

PALB2 p.Arg37Gly Uncertain significance ★★ ⚠ same residue
PALB2 p.Arg37Leu Uncertain significance ★★ ⚠ same residue
PALB2 p.Arg37Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
PALB2 p.Arg37His Conflicting classifications of pathogenicity ★ ⚠ same residue
PALB2 p.Arg37Pro Uncertain significance ★ ⚠ same residue
PALB2 p.Arg37= Likely benign ★ same residue
PALB2 p.Arg37fs Pathogenic ★ same residue
PALB2 c.3350+4A>G 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-arg37ser (accessed [today's date]).

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