Is PALB2 p.Ile48Phe (c.142A>T) pathogenic?

PALB2 p.Ile48Phe (c.142A>T) is classified Uncertain significance in PALB2 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.1035); Absent from gnomAD v4.1; Associated with breast-ovarian cancer, familial, susceptibility to, 1.

What condition is associated with PALB2 p.Ile48Phe (c.142A>T)?

PALB2 p.Ile48Phe (c.142A>T) is associated with breast-ovarian cancer, familial, susceptibility to, 1 (ClinVar).

How common is PALB2 p.Ile48Phe (c.142A>T) in the general population?

PALB2 p.Ile48Phe (c.142A>T) is absent from gnomAD v4.1 (gnomAD).

How is Hereditary breast and/or ovarian cancer syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PALB2 p.Ile48Phe (c.142A>T)?

AlphaMissense predicts likely benign (score 0.1035) — an in-silico prediction, not a clinical call.

PALB2 p.Ile48Phe

c.142A>T · rs786203134 · VCV1344535

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1035 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

breast-ovarian cancer, familial, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.1035	likely benign
REVEL	0.1	moderately benign-leaning
SaProt	LLR -7.43	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 -7.8	GERP -3.2
Regional constraint	o/e 1.00	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	0.022	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PALB2
Protein: p.Ile48Phe
Coding: c.142A>T
MANE Select: NM_024675
dbSNP: rs786203134
Type: single nucleotide variant
Location: chr16:23637919 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 48: 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-ovarian cancer, familial, susceptibility to, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary breast and/or ovarian cancer syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

PALB2 p.Ile48Val Uncertain significance ★★ ⚠ same residue
PALB2 p.Ile48Ser Uncertain significance ★ ⚠ same residue
PALB2 p.Arg1086Ter Pathogenic/Likely pathogenic ★★ same condition
PALB2 p.Arg414Ter Pathogenic/Likely pathogenic ★★ same condition
PALB2 p.Leu433Trp Uncertain significance ★★ ⚠ same condition
PALB2 p.Phe588Leu Uncertain significance ★★ ⚠ same condition
PALB2 p.Thr275Ile Uncertain significance ★★ ⚠ same condition
PALB2 p.Leu1046Pro Uncertain significance ★ ⚠ 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-ile48phe (accessed [today's date]).

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