Is PALB2 p.Pro4Leu (c.11C>T) pathogenic?

PALB2 p.Pro4Leu (c.11C>T) is classified Conflicting classifications of pathogenicity in PALB2 (ClinVar, Conflicting submitters, 17 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.0956); Ultra-rare (popmax 0.0242%, nfe); Associated with Breast and/or ovarian cancer.

What condition is associated with PALB2 p.Pro4Leu (c.11C>T)?

PALB2 p.Pro4Leu (c.11C>T) is associated with Breast and/or ovarian cancer, breast cancer, esophageal atresia/tracheoesophageal fistula (ClinVar).

How common is PALB2 p.Pro4Leu (c.11C>T) in the general population?

PALB2 p.Pro4Leu (c.11C>T) is ultra-rare (popmax 0.0242%, nfe) (gnomAD).

What do computational predictors say about PALB2 p.Pro4Leu (c.11C>T)?

AlphaMissense predicts likely benign (score 0.0956) — an in-silico prediction, not a clinical call.

PALB2 p.Pro4Leu

c.11C>T · rs45619737 · VCV126593

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 17 submitters

AlphaMissense

likely benign

0.0956 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0242%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Breast and/or ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.0956	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -5.75	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 1.7	GERP -1.5, phastCons 0.1
Regional constraint	o/e 1.00	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	17.74	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 0.0242% European (non-Finnish) · 285/1,179,850 alleles

Filtering AF 0.0218% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0209%

Overall 0.0188% 303/1,613,144 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0256%	3,899
European (non-Finnish)grpmax	0.0242%	4,140
African / African-American	0.00267%	37,453

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro4Leu
Coding: c.11C>T
MANE Select: NM_024675
dbSNP: rs45619737
Type: single nucleotide variant
Location: chr16:23641147 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 4: 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

Breast and/or ovarian cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: breast cancer esophageal atresia/tracheoesophageal fistula Fanconi anemia complementation group N pancreatic cancer, susceptibility to, 3 hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

PALB2 p.Pro4= Conflicting classifications of pathogenicity ★ same residue
PALB2 p.Pro4Ala Uncertain significance ★ ⚠ same residue
PALB2 p.Pro4Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
PALB2 p.Pro4Thr 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
PALB2 p.Gln692Ter 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-pro4leu (accessed [today's date]).

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