Is BAP1 p.Arg728His (c.2183G>A) pathogenic?

BAP1 p.Arg728His (c.2183G>A) is classified Uncertain significance in BAP1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-24). AlphaMissense: ambiguous (0.486); Very rare (popmax 0.00113%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with BAP1 p.Arg728His (c.2183G>A)?

BAP1 p.Arg728His (c.2183G>A) is associated with hereditary neoplastic syndrome, BAP1-related tumor predisposition syndrome (ClinVar).

How common is BAP1 p.Arg728His (c.2183G>A) in the general population?

BAP1 p.Arg728His (c.2183G>A) is very rare (popmax 0.00113%, sas) (gnomAD).

What do computational predictors say about BAP1 p.Arg728His (c.2183G>A)?

AlphaMissense predicts ambiguous (score 0.486) — an in-silico prediction, not a clinical call.

BAP1 p.Arg728His

c.2183G>A · rs773230722 · VCV1397331

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.486 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00113%, sas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.486	ambiguous
REVEL	0.304	indeterminate
SaProt	LLR -7.15	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP -0.45, phastCons 1
Overall
CADD	27.5	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 0.00113% South Asian · 1/88,426 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000437% 7/1,600,518 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00162%	61,854
Remaining individualsnot grpmax-eligible	0.00161%	61,998
South Asiangrpmax	0.00113%	88,426
European (non-Finnish)	0.00034%	293,801

Finnish 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.Arg728His
Coding: c.2183G>A
MANE Select: NM_007212 · reported on NM_004656
dbSNP: rs773230722
Type: single nucleotide variant
Location: chr3:52402295 (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

Also linked: BAP1-related tumor predisposition syndrome

Similar variants

BAP1 p.Arg728Cys Uncertain significance ★★ ⚠ same residue
BAP1 p.Arg728Pro Uncertain significance ★★ ⚠ same residue
BAP1 p.Arg728Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
BAP1 p.Arg728= 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

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-arg728his (accessed [today's date]).

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