Is BCL9 p.Pro516Ala (c.1546C>G) pathogenic?

BCL9 p.Pro516Ala (c.1546C>G) is classified Uncertain significance in BCL9 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-30). AlphaMissense: ambiguous (0.5442); Ultra-rare (popmax 0.0147%, afr).

How common is BCL9 p.Pro516Ala (c.1546C>G) in the general population?

BCL9 p.Pro516Ala (c.1546C>G) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

What do computational predictors say about BCL9 p.Pro516Ala (c.1546C>G)?

AlphaMissense predicts ambiguous (score 0.5442) — an in-silico prediction, not a clinical call.

BCL9 p.Pro516Ala

c.1546C>G · rs146055055 · VCV2397321

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5442 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Computational evidence

Protein change
AlphaMissense	0.5442	ambiguous
REVEL	0.387	indeterminate
SaProt	LLR -8.11	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 9,077 bp · p 0.29 · regional, not allelic
Overall
CADD	23.5	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 0.0147% African / African-American · 11/74,898 alleles

Filtering AF 0.00816% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.00316% 51/1,613,960 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0147%	6,809
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)	0.00288%	34,707
East Asian	0.00223%	44,876
South Asian	0.0022%	45,543

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.Pro516Ala
Coding: c.1546C>G
MANE Select: NM_004326
dbSNP: rs146055055
Type: single nucleotide variant
Location: chr1:147619701 (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 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
BCL9 p.Ala1407Gly 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-pro516ala (accessed [today's date]).

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