Is BAP1 p.Lys453fs (c.1358_1359del) pathogenic?

BAP1 p.Lys453fs (c.13581359del) is classified Pathogenic in BAP1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-08-11). Very rare (popmax 0.000169%, nfe); Associated with BAP1-related tumor predisposition syndrome.

What condition is associated with BAP1 p.Lys453fs (c.1358_1359del)?

BAP1 p.Lys453fs (c.1358_1359del) is associated with BAP1-related tumor predisposition syndrome, melanoma, uveal, susceptibility to, 2, hereditary neoplastic syndrome (ClinVar).

How common is BAP1 p.Lys453fs (c.1358_1359del) in the general population?

BAP1 p.Lys453fs (c.1358_1359del) is very rare (popmax 0.000169%, nfe) (gnomAD).

How is BAP1-related tumor predisposition syndrome inherited?

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

BAP1 p.Lys453fs

c.1358_1359del · rs1351986946 · VCV434478

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

BAP1-related tumor predisposition syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 13 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,026 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,114 alleles · very rare exomes 2/1,461,826 · genomes 0/152,288 · 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: BAP1
Protein: p.Lys453fs
Coding: c.1358_1359del
MANE Select: NM_004656
dbSNP: rs1351986946
Type: Deletion
Location: chr3:52403786 (GRCh38)
Gene constraint: LOEUF 0.324 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.87 · 4 PDB
Residue 453: a UniProt-annotated variant site (in tpds1)

Full BAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: melanoma, uveal, susceptibility to, 2 hereditary neoplastic syndrome Kury-Isidor syndrome

For BAP1-related tumor predisposition syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

BAP1 p.Lys453Glu Uncertain significance ★★ ⚠ same residue
BAP1 p.Lys453Thr Uncertain significance ★★ ⚠ same residue
BAP1 p.Lys453Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
BAP1 p.Lys453Gln Uncertain significance ★ ⚠ same residue
BAP1 p.Lys453= Likely benign ★ same residue
BAP1 c.123-10_129del Likely pathogenic ★★ same condition
BAP1 c.1729+1del Pathogenic ★★ same condition
BAP1 c.1984-3_1999del 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/bap1-p-lys453fs (accessed [today's date]).

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