Is BCR p.Pro229Ser (c.685C>T) pathogenic?

BCR p.Pro229Ser (c.685C>T) is classified Uncertain significance in BCR (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.0646); Very rare (popmax 0.00133%, afr); Associated with chronic myeloid leukemia.

What condition is associated with BCR p.Pro229Ser (c.685C>T)?

BCR p.Pro229Ser (c.685C>T) is associated with chronic myeloid leukemia, acute lymphoblastic leukemia (ClinVar).

How common is BCR p.Pro229Ser (c.685C>T) in the general population?

BCR p.Pro229Ser (c.685C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Chronic myeloid leukemia inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about BCR p.Pro229Ser (c.685C>T)?

AlphaMissense predicts likely benign (score 0.0646) — an in-silico prediction, not a clinical call.

BCR p.Pro229Ser

c.685C>T · rs1441856766 · VCV625895

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0646 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

chronic myeloid leukemia

Computational evidence

Protein change
AlphaMissense	0.0646	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -5.82	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 -0.33	GERP -0.26, phastCons 0.002
Regional constraint	o/e 1.27	unconstrained · MANE · 73 kb · p 1.1e-11 · regional, not allelic
Overall
CADD	9.417	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 0.00133% African / African-American · 1/74,944 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,609,564 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,944
European (non-Finnish)	0.00017%	589,967

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.Pro229Ser
Coding: c.685C>T
MANE Select: NM_004327
dbSNP: rs1441856766
Type: single nucleotide variant
Location: chr22:23181645 (GRCh38)
Gene constraint: LOEUF 0.608 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 65.61 · 5 PDB
Residue 229: the 'kinase' region; the 'disordered' region; the 'binding to abl sh2-domain' region

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

Disease context

chronic myeloid leukemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: acute lymphoblastic leukemia

For Chronic myeloid leukemia (Orphanet):

Inheritance: Not applicable
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

BCR p.Ser202= Benign/Likely benign ★★ same condition
BCR p.Ala786Thr Uncertain significance ★ ⚠ same condition
BCR p.Pro383= Uncertain significance ★ same condition
BCR p.Val1094fs Conflicting classifications of pathogenicity ★ same condition
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

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-pro229ser (accessed [today's date]).

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