Is BAP1 p.Ala323Thr (c.967G>A) pathogenic?

BAP1 p.Ala323Thr (c.967G>A) is classified Uncertain significance in BAP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-12-04). AlphaMissense: likely benign (0.0623); Very rare (popmax 8.47e-05%, nfe); Associated with BAP1-related tumor predisposition syndrome.

What condition is associated with BAP1 p.Ala323Thr (c.967G>A)?

BAP1 p.Ala323Thr (c.967G>A) is associated with BAP1-related tumor predisposition syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BAP1 p.Ala323Thr (c.967G>A) in the general population?

BAP1 p.Ala323Thr (c.967G>A) is very rare (popmax 8.47e-05%, 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.Ala323Thr (c.967G>A)?

AlphaMissense predicts likely benign (score 0.0623) — an in-silico prediction, not a clinical call.

BAP1 p.Ala323Thr

c.967G>A · rs1559588616 · VCV629725

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0623 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

BAP1-related tumor predisposition syndrome

Computational evidence

Protein change
AlphaMissense	0.0623	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -5.86	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.35 · evaluated, not missing
Pangolin	Δ0.26	gain · loss 0.16 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 4.1	GERP 1.9, phastCons 1
Overall
CADD	18.82	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 8.47e-05% European (non-Finnish) · 1/1,180,016 alleles

Overall 6.84e-05% 1/1,461,642 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.Ala323Thr
Coding: c.967G>A
MANE Select: NM_007212 · reported on NM_004656
dbSNP: rs1559588616
Type: single nucleotide variant
Location: chr3:52405259 (GRCh38)
Structure: AlphaFold pLDDT 78.27 · 28 PDB
Residue 323: a cross-link site; a β-strand

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.Ala323= Likely benign ★★ same residue
BAP1 p.Ala323Gly Uncertain significance ★ same residue
BAP1 p.Ala323Ser Uncertain significance ★ ⚠ same residue
BAP1 p.Ala323Val 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

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-ala323thr (accessed [today's date]).

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