Is BCR p.Arg649His (c.1946G>A) pathogenic?

BCR p.Arg649His (c.1946G>A) is classified Uncertain significance in BCR (ClinVar, Single submitter, 2 submitters; last evaluated 2025-11-13). AlphaMissense: likely pathogenic (0.9677); Very rare (popmax 0.00666%, amr).

How common is BCR p.Arg649His (c.1946G>A) in the general population?

BCR p.Arg649His (c.1946G>A) is very rare (popmax 0.00666%, amr) (gnomAD).

What do computational predictors say about BCR p.Arg649His (c.1946G>A)?

AlphaMissense predicts likely pathogenic (score 0.9677) — an in-silico prediction, not a clinical call.

BCR p.Arg649His

c.1946G>A · VCV4456532

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9677 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9677	likely pathogenic
REVEL	0.881	moderately pathogenic-leaning
SaProt	LLR -9.54	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 57 kb · p 4.3e-10 · regional, not allelic
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 0.00666% Admixed American · 4/60,024 alleles

Filtering AF 0.00225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00124% 20/1,613,514 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00666%	15,006
East Asian	0.00223%	44,864
European (non-Finnish)	0.00119%	84,264
South Asian	0.0011%	91,072

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: BCR
Protein: p.Arg649His
Coding: c.1946G>A
MANE Select: NM_004327
Type: single nucleotide variant
Location: chr22:23273105 (GRCh38)
Gene constraint: LOEUF 0.608 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 65.61 · 5 PDB
Residue 649: the dh domain; an α-helix

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

Similar variants

BCR p.Ser356Arg Uncertain significance ★★ ⚠ same type
BCR c.2116-6C>G Benign/Likely benign ★★ same type
BCR c.2116-7C>A Benign/Likely benign ★★ same type
BCR c.2526+7G>T Benign/Likely benign ★★ same type
BCR c.3073-8T>C Benign ★★ same type
BCR c.3183-4G>A Benign ★★ same type
BCR p.Ala1257= Benign/Likely benign ★★ same type
BCR p.Ala152Val Benign ★★ ⚠ 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/bcr-p-arg649his (accessed [today's date]).

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