Is PALB2 p.Leu583Trp (c.1748T>G) pathogenic?

PALB2 p.Leu583Trp (c.1748T>G) is classified Uncertain significance in PALB2 (ClinVar, Expert panel, 16 submitters; last evaluated 2023-04-05). AlphaMissense: likely benign (0.1335); Ultra-rare (popmax 0.0164%, mid); Associated with PALB2-related cancer predisposition.

What condition is associated with PALB2 p.Leu583Trp (c.1748T>G)?

PALB2 p.Leu583Trp (c.1748T>G) is associated with PALB2-related cancer predisposition, Fanconi anemia complementation group N, pancreatic cancer, susceptibility to, 3 (ClinVar).

How common is PALB2 p.Leu583Trp (c.1748T>G) in the general population?

PALB2 p.Leu583Trp (c.1748T>G) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about PALB2 p.Leu583Trp (c.1748T>G)?

AlphaMissense predicts likely benign (score 0.1335) — an in-silico prediction, not a clinical call.

PALB2 p.Leu583Trp

c.1748T>G · rs587782151 · VCV141972

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 16 submitters

AlphaMissense

likely benign

0.1335 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 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.1748T>G (p.Leu583Trp) variant in PALB2 is a missense variant predicted to cause a substitution of leucine by tryptophan at amino acid 583 (p.Leu583Trp). This variant has a minor allele frequency in gnomAD v2.1.1 of 0.000044 in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). 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	0.1335	likely benign
REVEL	0.113	moderately benign-leaning
SaProt	LLR -8.85	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.42	GERP 1.8
Regional constraint	o/e 1.00	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	19.36	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

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.00297% 48/1,613,996 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0064%	15,621
European (non-Finnish)	0.00339%	29,500
Admixed American	0.00333%	30,000
African / African-American	0.00133%	74,928

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.Leu583Trp
Coding: c.1748T>G
MANE Select: NM_024675
dbSNP: rs587782151
Type: single nucleotide variant
Location: chr16:23630406 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 583: 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

Also linked: Fanconi anemia complementation group N pancreatic cancer, susceptibility to, 3 hereditary neoplastic syndrome hereditary breast carcinoma breast-ovarian cancer, familial, susceptibility to, 5

Similar variants

PALB2 p.Leu583Phe Uncertain significance ★ ⚠ same residue
PALB2 p.Leu583Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
PALB2 p.Leu583= Likely benign ★ 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
PALB2 p.Glu3Ter 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-leu583trp (accessed [today's date]).

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