Is BCL9 p.Pro1398Leu (c.4193C>T) pathogenic?

BCL9 p.Pro1398Leu (c.4193C>T) is classified Uncertain significance in BCL9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-26). AlphaMissense: likely pathogenic (0.7719); Ultra-rare (popmax 0.0533%, afr).

How common is BCL9 p.Pro1398Leu (c.4193C>T) in the general population?

BCL9 p.Pro1398Leu (c.4193C>T) is ultra-rare (popmax 0.0533%, afr) (gnomAD).

What do computational predictors say about BCL9 p.Pro1398Leu (c.4193C>T)?

AlphaMissense predicts likely pathogenic (score 0.7719) — an in-silico prediction, not a clinical call.

BCL9 p.Pro1398Leu

c.4193C>T · rs150292509 · VCV2264479

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7719 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0533%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7719	likely pathogenic
REVEL	0.169	moderately benign-leaning
SaProt	LLR -10.12	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.99, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 4,041 bp · p 0.00021 · regional, not allelic
Overall
CADD	23.3	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 0.0533% African / African-American · 40/74,984 alleles

Filtering AF 0.0402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0356%

Overall 0.00291% 47/1,613,960 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0533%	1,875
Middle Eastern	0.0165%	6,058
Remaining individualsnot grpmax-eligible	0.0064%	15,627
European (non-Finnish)	0.000169%	589,977

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: BCL9
Protein: p.Pro1398Leu
Coding: c.4193C>T
MANE Select: NM_004326
dbSNP: rs150292509
Type: single nucleotide variant
Location: chr1:147624871 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 43.07 · 8 PDB

Full BCL9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BCL9 p.Pro1398Gln Uncertain significance ★ ⚠ same residue
BCL9 c.661-8G>T Benign/Likely benign ★★ same type
BCL9 p.Arg485= Benign ★★ same type
BCL9 p.Ala1042Thr Uncertain significance ★ ⚠ same type
BCL9 p.Ala1190Val Uncertain significance ★ ⚠ same type
BCL9 p.Ala1281Asp Uncertain significance ★ ⚠ same type
BCL9 p.Ala128Pro Uncertain significance ★ ⚠ same type
BCL9 p.Ala1337Val Uncertain significance ★ ⚠ same type

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/bcl9-p-pro1398leu (accessed [today's date]).

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