Is BAP1 p.Ser126Arg (c.378C>A) pathogenic?

BAP1 p.Ser126Arg (c.378C>A) is classified Uncertain significance in BAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-14). AlphaMissense: likely pathogenic (0.9969); Absent from gnomAD v4.1; Associated with BAP1-related tumor predisposition syndrome.

What condition is associated with BAP1 p.Ser126Arg (c.378C>A)?

BAP1 p.Ser126Arg (c.378C>A) is associated with BAP1-related tumor predisposition syndrome (ClinVar).

How common is BAP1 p.Ser126Arg (c.378C>A) in the general population?

BAP1 p.Ser126Arg (c.378C>A) is absent from gnomAD v4.1 (gnomAD).

How is BAP1-related tumor predisposition syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about BAP1 p.Ser126Arg (c.378C>A)?

AlphaMissense predicts likely pathogenic (score 0.9969) — an in-silico prediction, not a clinical call.

BAP1 p.Ser126Arg

c.378C>A · rs746830670 · VCV2709392

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9969 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

BAP1-related tumor predisposition syndrome

Computational evidence

Protein change
AlphaMissense	0.9969	likely pathogenic
REVEL	0.228	benign-leaning
SaProt	LLR -7.46	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.7	GERP 1.8, phastCons 1
Overall
CADD	25.8	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.Ser126Arg
Coding: c.378C>A
MANE Select: NM_007212 · reported on NM_004656
dbSNP: rs746830670
Type: single nucleotide variant
Location: chr3:52407458 (GRCh38)
Structure: AlphaFold pLDDT 78.27 · 28 PDB
Residue 126: the 'interaction with hip2' region

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

Disease context

BAP1-related tumor predisposition syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For BAP1-related tumor predisposition syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

BAP1 p.Ser126Asn Uncertain significance ★★ ⚠ same residue
BAP1 p.Ser126= 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

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-ser126arg (accessed [today's date]).

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