Is CPB2 p.Asp226= (c.678T>C) pathogenic?

CPB2 p.Asp226= (c.678T>C) is classified Benign in CPB2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-17). Common (popmax 38.8%, afr) — too common for a highly-penetrant pathogenic allele; Associated with CPB2-related disorder.

What condition is associated with CPB2 p.Asp226= (c.678T>C)?

CPB2 p.Asp226= (c.678T>C) is associated with CPB2-related disorder (ClinVar).

CPB2 p.Asp226=

Q: How common is CPB2 p.Asp226= (c.678T>C) in the general population?

CPB2 p.Asp226= (c.678T>C) is common (popmax 38.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.678T>C · rs9316179 · VCV3059117

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 38.8%, afr) — 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 carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.37 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.14	GERP -3.8, phastCons 0.079
Overall
CADD	7.035	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 38.8% African / African-American · 28,481/73,460 alleles

Filtering AF 38.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 38.2%

Overall 31.5% 488,953/1,553,388 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	39.5%	3
African / African-Americangrpmax	38.8%	3
Ashkenazi Jewishnot grpmax-eligible	34.7%	3
Middle Eastern	31.6%	3
European (non-Finnish)	31.6%	3
Remaining individualsnot grpmax-eligible	31.5%	3
Admixed American	30.3%	3
Amishnot grpmax-eligible	28.8%	3
East Asian	25.7%	4
South Asian	21.3%	5

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp226=
Coding: c.678T>C
MANE Select: NM_001872
dbSNP: rs9316179
Type: single nucleotide variant
Location: chr13:46067331 (GRCh38)
Gene constraint: LOEUF 1.373 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.32 · 10 PDB
Residue 226: the peptidase m14 domain; an α-helix

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.Asp97= Benign same condition
CPB2 p.Cys405= Likely benign same condition
CPB2 p.Glu184= Likely benign same condition
CPB2 p.Ile251= 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-asp226 (accessed [today's date]).

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