Is BAP1 p.Lys249Asn (c.747G>T) pathogenic?

BAP1 p.Lys249Asn (c.747G>T) is classified Conflicting classifications of pathogenicity in BAP1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-05-05). AlphaMissense: likely pathogenic (0.9878); Very rare (popmax 0.000274%); Associated with hereditary neoplastic syndrome.

What condition is associated with BAP1 p.Lys249Asn (c.747G>T)?

BAP1 p.Lys249Asn (c.747G>T) is associated with hereditary neoplastic syndrome, BAP1-related tumor predisposition syndrome (ClinVar).

How common is BAP1 p.Lys249Asn (c.747G>T) in the general population?

BAP1 p.Lys249Asn (c.747G>T) is very rare (popmax 0.000274%) (gnomAD).

What do computational predictors say about BAP1 p.Lys249Asn (c.747G>T)?

AlphaMissense predicts likely pathogenic (score 0.9878) — an in-silico prediction, not a clinical call.

BAP1 p.Lys249Asn

c.747G>T · rs1553645603 · VCV489643

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9878 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000274%)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9878	likely pathogenic
REVEL	0.297	indeterminate
SaProt	LLR -6.14	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -1.5, phastCons 1
Overall
CADD	23.5	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 0.000274%

Overall 0.000274% 4/1,461,858 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,835
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606

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: BAP1
Protein: p.Lys249Asn
Coding: c.747G>T
MANE Select: NM_007212 · reported on NM_004656
dbSNP: rs1553645603
Type: single nucleotide variant
Location: chr3:52406289 (GRCh38)
Structure: AlphaFold pLDDT 78.27 · 28 PDB
Residue 249: a cross-link site; a β-strand

Full BAP1 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: BAP1-related tumor predisposition syndrome

Similar variants

BAP1 p.Lys249= Benign/Likely benign ★★ same residue
BAP1 c.1117-1G>A Likely pathogenic ★★ same condition
BAP1 c.122+1G>A Pathogenic ★★ same condition
BAP1 c.122+1G>T Pathogenic/Likely pathogenic ★★ same condition
BAP1 c.122+5G>A Pathogenic/Likely pathogenic ★★ same condition
BAP1 c.122+5G>C Likely pathogenic ★★ same condition
BAP1 c.1251-1G>A Likely pathogenic ★★ same condition
BAP1 c.1251-1G>C 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-lys249asn (accessed [today's date]).

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