Is BCR p.Pro253Ser (c.757C>T) pathogenic?

BCR p.Pro253Ser (c.757C>T) is classified Uncertain significance in BCR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-28). AlphaMissense: likely benign (0.1407); Very rare (popmax 0.00223%, eas).

How common is BCR p.Pro253Ser (c.757C>T) in the general population?

BCR p.Pro253Ser (c.757C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about BCR p.Pro253Ser (c.757C>T)?

AlphaMissense predicts likely benign (score 0.1407) — an in-silico prediction, not a clinical call.

BCR p.Pro253Ser

c.757C>T · rs1027510281 · VCV2490647

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1407 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1407	likely benign
REVEL	0.1	moderately benign-leaning
SaProt	LLR -5.55	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 3.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 73 kb · p 1.1e-11 · regional, not allelic
Overall
CADD	23.3	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 0.00223% East Asian · 1/44,874 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000436% 7/1,603,986 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,874
Finnishnot grpmax-eligible	0.00185%	53,990
Remaining individualsnot grpmax-eligible	0.0016%	62,444
African / African-American	0.00133%	75,044
European (non-Finnish)	0.000254%	393,320

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.Pro253Ser
Coding: c.757C>T
MANE Select: NM_004327
dbSNP: rs1027510281
Type: single nucleotide variant
Location: chr22:23181717 (GRCh38)
Gene constraint: LOEUF 0.608 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 65.61 · 5 PDB
Residue 253: the 'kinase' region; the 'binding to abl sh2-domain' region

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

Similar variants

BCR p.Pro253Arg Uncertain significance ★ ⚠ same residue
BCR p.Pro253Leu Uncertain significance ★ ⚠ same residue
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

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-pro253ser (accessed [today's date]).

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