Is PALB2 p.His693Pro (c.2078A>C) pathogenic?

PALB2 p.His693Pro (c.2078A>C) is classified Uncertain significance in PALB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-13). AlphaMissense: likely benign (0.0566); Very rare (popmax 0.00133%, afr).

How common is PALB2 p.His693Pro (c.2078A>C) in the general population?

PALB2 p.His693Pro (c.2078A>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about PALB2 p.His693Pro (c.2078A>C)?

AlphaMissense predicts likely benign (score 0.0566) — an in-silico prediction, not a clinical call.

PALB2 p.His693Pro

c.2078A>C · VCV4079491

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0566 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0566	likely benign
REVEL	0.005	strongly benign-leaning
SaProt	LLR -5.55	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 0.45	GERP -3
Regional constraint	o/e 1.00	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	0.018	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 0.00133% African / African-American · 1/75,060 alleles

Overall 6.19e-05% 1/1,614,230 alleles · very rare exomes 1/1,461,892 · genomes 0/152,338 · 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.His693Pro
Coding: c.2078A>C
MANE Select: NM_024675
Type: single nucleotide variant
Location: chr16:23630076 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 693: the 'disordered' region; 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

Similar variants

PALB2 p.His693Asn Uncertain significance ★★ ⚠ same residue
PALB2 p.His693= Benign/Likely benign ★★ same residue
PALB2 p.His693Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
PALB2 p.His693Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
PALB2 p.His693fs Pathogenic ★★ same residue
PALB2 c.3350+4A>G Likely pathogenic ★★★ same type
PALB2 p.Arg1117Lys Pathogenic ★★★ ⚠ same type
PALB2 p.Gln228Ter Pathogenic ★★★ same type

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-his693pro (accessed [today's date]).

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