Is BAP1 p.Leu440Pro (c.1319T>C) pathogenic?

BAP1 p.Leu440Pro (c.1319T>C) is classified Uncertain significance in BAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-05). AlphaMissense: ambiguous (0.4605); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with BAP1 p.Leu440Pro (c.1319T>C)?

BAP1 p.Leu440Pro (c.1319T>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is BAP1 p.Leu440Pro (c.1319T>C) in the general population?

BAP1 p.Leu440Pro (c.1319T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BAP1 p.Leu440Pro (c.1319T>C)?

AlphaMissense predicts ambiguous (score 0.4605) — an in-silico prediction, not a clinical call.

BAP1 p.Leu440Pro

c.1319T>C · rs1553644982 · VCV490792

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4605 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4605	ambiguous
REVEL	0.274	benign-leaning
SaProt	LLR -6.08	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.35 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Overall
CADD	23.4	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

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: BAP1
Protein: p.Leu440Pro
Coding: c.1319T>C
MANE Select: NM_007212 · reported on NM_004656
dbSNP: rs1553644982
Type: single nucleotide variant
Location: chr3:52403826 (GRCh38)
Structure: AlphaFold pLDDT 78.27 · 28 PDB

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

Similar variants

BAP1 p.Leu440Arg Uncertain significance ★ ⚠ same residue
BAP1 p.Leu440= Likely benign ★ same residue
BAP1 p.Leu440Val 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.1251-1G>A Likely pathogenic ★★ same condition
BAP1 c.1251-2A>G 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-leu440pro (accessed [today's date]).

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