Is BAP1 p.Arg417Gly (c.1249A>G) pathogenic?

BAP1 p.Arg417Gly (c.1249A>G) is classified Uncertain significance in BAP1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-16). AlphaMissense: likely benign (0.1748); Very rare (popmax 0.005%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with BAP1 p.Arg417Gly (c.1249A>G)?

BAP1 p.Arg417Gly (c.1249A>G) is associated with hereditary neoplastic syndrome, BAP1-related tumor predisposition syndrome (ClinVar).

How common is BAP1 p.Arg417Gly (c.1249A>G) in the general population?

BAP1 p.Arg417Gly (c.1249A>G) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about BAP1 p.Arg417Gly (c.1249A>G)?

AlphaMissense predicts likely benign (score 0.1748) — an in-silico prediction, not a clinical call.

BAP1 p.Arg417Gly

c.1249A>G · rs767064896 · VCV650159

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1748 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1748	likely benign
REVEL	0.273	benign-leaning
SaProt	LLR -5.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.47	loss · gain 0.33 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 5.1	GERP 0.57, phastCons 1
Overall
CADD	26.8	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 0.005% Admixed American · 3/60,008 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000991% 16/1,614,106 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,003
African / African-American	0.00267%	37,469
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.000847%	118,004

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.Arg417Gly
Coding: c.1249A>G
MANE Select: NM_004656
dbSNP: rs767064896
Type: single nucleotide variant
Location: chr3:52404454 (GRCh38)
Gene constraint: LOEUF 0.324 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.87 · 4 PDB
Residue 417: 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

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.Arg417= Conflicting classifications of pathogenicity ★ same residue
BAP1 p.Arg417Lys Uncertain significance ★ ⚠ same residue
BAP1 p.Arg417Ser 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

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-arg417gly (accessed [today's date]).

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