Is BAP1 p.Thr444Ala (c.1330A>G) pathogenic?

BAP1 p.Thr444Ala (c.1330A>G) is classified Conflicting classifications of pathogenicity in BAP1 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.1285); Ultra-rare (popmax 0.0813%, afr); Associated with BAP1-related tumor predisposition syndrome.

What condition is associated with BAP1 p.Thr444Ala (c.1330A>G)?

BAP1 p.Thr444Ala (c.1330A>G) is associated with BAP1-related tumor predisposition syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BAP1 p.Thr444Ala (c.1330A>G) in the general population?

BAP1 p.Thr444Ala (c.1330A>G) is ultra-rare (popmax 0.0813%, afr) (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.Thr444Ala (c.1330A>G)?

AlphaMissense predicts likely benign (score 0.1285) — an in-silico prediction, not a clinical call.

BAP1 p.Thr444Ala

c.1330A>G · rs374746213 · VCV412441

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.1285 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0813%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

BAP1-related tumor predisposition syndrome

Computational evidence

Protein change
AlphaMissense	0.1285	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -6.09	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Overall
CADD	21.2	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 0.0813% African / African-American · 61/75,006 alleles

Filtering AF 0.0649% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.059%

Overall 0.00415% 67/1,614,090 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0813%	1,230
Remaining individualsnot grpmax-eligible	0.0064%	15,628
Admixed American	0.00333%	30,005

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.Thr444Ala
Coding: c.1330A>G
MANE Select: NM_004656
dbSNP: rs374746213
Type: single nucleotide variant
Location: chr3:52403815 (GRCh38)
Gene constraint: LOEUF 0.324 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.87 · 4 PDB
Residue 444: a UniProt-annotated variant site (in tpds1)

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.Thr444= Likely benign ★★ same residue
BAP1 p.Thr444Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
BAP1 p.Thr444Pro Uncertain significance ★ ⚠ same residue
BAP1 p.Thr444Ser 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-thr444ala (accessed [today's date]).

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