Is CPB2 p.Ile251= (c.753C>T) pathogenic?

CPB2 p.Ile251= (c.753C>T) is classified Benign in CPB2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-11-19). Common (popmax 28.8%, eas) — too common for a highly-penetrant pathogenic allele; Associated with CPB2-related disorder.

What condition is associated with CPB2 p.Ile251= (c.753C>T)?

CPB2 p.Ile251= (c.753C>T) is associated with CPB2-related disorder (ClinVar).

CPB2 p.Ile251=

Q: How common is CPB2 p.Ile251= (c.753C>T) in the general population?

CPB2 p.Ile251= (c.753C>T) is common (popmax 28.8%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.753C>T · rs2277440 · VCV3059439

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 28.8%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

CPB2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.26	acceptor loss, 50 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -4.5	GERP -5.5
Overall
CADD	0.854	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 28.8% East Asian · 12,913/44,838 alleles

Filtering AF 28.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 28.2%

Overall 8.05% 129,853/1,613,616 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	28.8%	3
Admixed American	17.7%	6
African / African-American	11.6%	9
South Asian	11.5%	9
Middle Eastern	9.58%	10
Remaining individualsnot grpmax-eligible	9.18%	11
Ashkenazi Jewishnot grpmax-eligible	7.01%	14
European (non-Finnish)	6.45%	16
Finnishnot grpmax-eligible	4.17%	24
Amishnot grpmax-eligible	3.73%	27

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: CPB2
Protein: p.Ile251=
Coding: c.753C>T
MANE Select: NM_001872
dbSNP: rs2277440
Type: single nucleotide variant
Location: chr13:46064691 (GRCh38)
Gene constraint: LOEUF 1.373 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.32 · 10 PDB
Residue 251: a disulfide bond; the peptidase m14 domain

Full CPB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CPB2-related disorder

Similar variants

CPB2 p.Ala169Thr Benign same condition
CPB2 p.Asp226= Benign same condition
CPB2 p.Asp97= Benign same condition
CPB2 p.Cys405= Likely benign same condition
CPB2 p.Glu184= Likely benign same condition
CPB2 p.Ile347Thr Benign ⚠ same condition
CPB2 p.Pro221= Benign same condition
CPB2 p.Gly203_Ile204insTer Uncertain significance same condition

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/cpb2-p-ile251 (accessed [today's date]).

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