Is BAP1 p.Pro42Ser (c.124C>T) pathogenic?

BAP1 p.Pro42Ser (c.124C>T) is classified Conflicting classifications of pathogenicity in BAP1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-18). AlphaMissense: likely pathogenic (0.8812); Very rare (popmax 0.00017%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BAP1 p.Pro42Ser (c.124C>T)?

BAP1 p.Pro42Ser (c.124C>T) is associated with hereditary neoplastic syndrome, BAP1-related tumor predisposition syndrome (ClinVar).

How common is BAP1 p.Pro42Ser (c.124C>T) in the general population?

BAP1 p.Pro42Ser (c.124C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about BAP1 p.Pro42Ser (c.124C>T)?

AlphaMissense predicts likely pathogenic (score 0.8812) — an in-silico prediction, not a clinical call.

BAP1 p.Pro42Ser

c.124C>T · rs1467630034 · VCV1056010

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8812 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.8812	likely pathogenic
REVEL	0.532	indeterminate
SaProt	LLR -11.33	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Overall
CADD	33.0	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 0.00017% European (non-Finnish) · 2/1,177,884 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,608,914 alleles · very rare

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.Pro42Ser
Coding: c.124C>T
MANE Select: NM_007212 · reported on NM_004656
dbSNP: rs1467630034
Type: single nucleotide variant
Location: chr3:52408605 (GRCh38)
Structure: AlphaFold pLDDT 78.27 · 28 PDB
Residue 42: the 'interaction with hip2' region; an α-helix

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.Pro42Leu Uncertain significance ★★ ⚠ same residue
BAP1 p.Pro42Arg Uncertain significance ★ ⚠ same residue
BAP1 p.Pro42His Uncertain significance ★ ⚠ same residue
BAP1 p.Pro42Thr Uncertain significance ★ ⚠ same residue
BAP1 p.Pro42= Likely benign ★ same residue
BAP1 p.Pro42fs Pathogenic ★ same residue
BAP1 c.1117-1G>A Likely pathogenic ★★ same condition
BAP1 c.122+1G>A 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-pro42ser (accessed [today's date]).

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