Is PALB2 p.Arg40Ser (c.120A>T) pathogenic?

PALB2 p.Arg40Ser (c.120A>T) is classified Uncertain significance in PALB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-17). AlphaMissense: likely pathogenic (0.7765); Very rare (popmax 0.000254%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with PALB2 p.Arg40Ser (c.120A>T)?

PALB2 p.Arg40Ser (c.120A>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is PALB2 p.Arg40Ser (c.120A>T) in the general population?

PALB2 p.Arg40Ser (c.120A>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about PALB2 p.Arg40Ser (c.120A>T)?

AlphaMissense predicts likely pathogenic (score 0.7765) — an in-silico prediction, not a clinical call.

PALB2 p.Arg40Ser

c.120A>T · VCV3413498

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7765 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.7765	likely pathogenic · top 5% in PALB2
REVEL	0.104	moderately benign-leaning
SaProt	LLR -8.07	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 3.4	GERP 0.58, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	21.9	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 0.000254% European (non-Finnish) · 3/1,179,822 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,944 alleles · very rare exomes 3/1,461,634 · genomes 0/152,310 · joint denominator

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.Arg40Ser
Coding: c.120A>T
MANE Select: NM_024675
Type: single nucleotide variant
Location: chr16:23637941 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 40: the 'interaction with rad51' region; the 'required for its oligomerization and is important for its focal concentration at dna damage sites' region; 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

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

Similar variants

PALB2 p.Arg40Thr Uncertain significance ★★ ⚠ same residue
PALB2 p.Arg40= Likely benign ★★ same residue
PALB2 p.Arg40Ile Uncertain significance ★ ⚠ same residue
PALB2 p.Arg40Lys Conflicting classifications of pathogenicity ★ ⚠ same residue
PALB2 p.Arg40fs Pathogenic ★★ 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-arg40ser (accessed [today's date]).

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