Is BAP1 p.Gly41Ala (c.122G>C) pathogenic?

BAP1 p.Gly41Ala (c.122G>C) is classified Conflicting classifications of pathogenicity in BAP1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-12-17). AlphaMissense: ambiguous (0.3501); Very rare (popmax 0.000508%, nfe); Associated with BAP1-related tumor predisposition syndrome.

What condition is associated with BAP1 p.Gly41Ala (c.122G>C)?

BAP1 p.Gly41Ala (c.122G>C) is associated with BAP1-related tumor predisposition syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BAP1 p.Gly41Ala (c.122G>C) in the general population?

BAP1 p.Gly41Ala (c.122G>C) is very rare (popmax 0.000508%, nfe) (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.Gly41Ala (c.122G>C)?

AlphaMissense predicts ambiguous (score 0.3501) — an in-silico prediction, not a clinical call.

BAP1 p.Gly41Ala

c.122G>C · rs1553646278 · VCV539927

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3501 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

BAP1-related tumor predisposition syndrome

Computational evidence

Protein change
AlphaMissense	0.3501	ambiguous
REVEL	0.225	benign-leaning
SaProt	LLR -7.02	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.96 · evaluated, not missing
Pangolin	Δ0.21	loss · gain 0.06 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 1.4, 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 0.000508% European (non-Finnish) · 6/1,180,008 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.00041% 6/1,461,876 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.Gly41Ala
Coding: c.122G>C
MANE Select: NM_007212 · reported on NM_004656
dbSNP: rs1553646278
Type: single nucleotide variant
Location: chr3:52409554 (GRCh38)
Structure: AlphaFold pLDDT 78.27 · 28 PDB
Residue 41: the 'interaction with hip2' region; a modified residue (phosphoserine)

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

Disease context

Also linked: hereditary neoplastic syndrome

For BAP1-related tumor predisposition syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

BAP1 p.Gly41Ser Benign/Likely benign ★★ same residue
BAP1 p.Gly41= Conflicting classifications of pathogenicity ★ same residue
BAP1 p.Gly41Arg Uncertain significance ★ ⚠ same residue
BAP1 p.Gly41Asp Uncertain significance ★ ⚠ same residue
BAP1 p.Gly41Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
BAP1 p.Gly41Val Uncertain significance ★ ⚠ 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-gly41ala (accessed [today's date]).

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