Is PALB2 p.His83Pro (c.248A>C) pathogenic?

PALB2 p.His83Pro (c.248A>C) is classified Uncertain significance in PALB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-26). AlphaMissense: likely benign (0.0789); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with PALB2 p.His83Pro (c.248A>C)?

PALB2 p.His83Pro (c.248A>C) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is PALB2 p.His83Pro (c.248A>C) in the general population?

PALB2 p.His83Pro (c.248A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PALB2 p.His83Pro (c.248A>C)?

AlphaMissense predicts likely benign (score 0.0789) — an in-silico prediction, not a clinical call.

PALB2 p.His83Pro

c.248A>C · rs2142447708 · VCV1516025

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0789 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0789	likely benign
REVEL	0.155	moderately benign-leaning
SaProt	LLR -5.51	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 2.3	GERP 0.79, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	18.89	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.His83Pro
Coding: c.248A>C
MANE Select: NM_024675
dbSNP: rs2142447708
Type: single nucleotide variant
Location: chr16:23636298 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 83: 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

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

Also linked: hereditary breast carcinoma

Similar variants

PALB2 p.His83= Benign/Likely benign ★★ same residue
PALB2 p.His83Arg Uncertain significance ★ ⚠ same residue
PALB2 p.His83Asn Uncertain significance ★ ⚠ same residue
PALB2 p.His83Asp Uncertain significance ★ ⚠ same residue
PALB2 p.His83Tyr Uncertain significance ★ ⚠ same residue
PALB2 p.His83fs Pathogenic ★★ same residue
PALB2 c.3350+4A>G Likely pathogenic ★★★ same condition
PALB2 p.Arg1117Lys 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-his83pro (accessed [today's date]).

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