Is BAP1 p.Leu334= (c.1002A>G) pathogenic?

BAP1 p.Leu334= (c.1002A>G) is classified Benign/Likely benign in BAP1 (ClinVar, Multiple submitters, 19 submitters; last evaluated 2026-02-04). Low-frequency (popmax 2.33%, sas); Associated with melanoma, uveal, susceptibility to, 2.

What condition is associated with BAP1 p.Leu334= (c.1002A>G)?

BAP1 p.Leu334= (c.1002A>G) is associated with melanoma, uveal, susceptibility to, 2, BAP1-related tumor predisposition syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BAP1 p.Leu334= (c.1002A>G) in the general population?

BAP1 p.Leu334= (c.1002A>G) is low-frequency (popmax 2.33%, sas) (gnomAD).

BAP1 p.Leu334=

c.1002A>G · rs28997577 · VCV220641

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 19 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.33%, sas)

Conditions

melanoma, uveal, susceptibility to, 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.15	GERP 0.82, phastCons 0.9
Overall
CADD	10.38	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.33% South Asian · 2,121/91,082 alleles

Filtering AF 2.25% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.21%

Overall 0.567% 9,154/1,614,056 alleles · low-frequency exomes 8,566/1,461,782 · genomes 588/152,274 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	2.33%	43
East Asian	0.793%	126
Remaining individualsnot grpmax-eligible	0.55%	182
Middle Eastern	0.511%	196
European (non-Finnish)	0.504%	198
Admixed American	0.247%	406
Ashkenazi Jewishnot grpmax-eligible	0.166%	604
Finnishnot grpmax-eligible	0.15%	666
African / African-American	0.076%	1,317

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.Leu334=
Coding: c.1002A>G
MANE Select: NM_004656
dbSNP: rs28997577
Type: single nucleotide variant
Location: chr3:52405224 (GRCh38)
Gene constraint: LOEUF 0.324 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.87 · 4 PDB
Residue 334: the 'disordered' region; a UniProt-annotated variant site (in tpds1)

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

Disease context

melanoma, uveal, susceptibility to, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: BAP1-related tumor predisposition syndrome hereditary neoplastic syndrome

Similar variants

BAP1 p.Leu334Ile Uncertain significance ★★ ⚠ 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-leu334 (accessed [today's date]).

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