Is CPB2 p.Trp264Arg (c.790T>C) pathogenic?

CPB2 p.Trp264Arg (c.790T>C) is classified Uncertain significance in CPB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-24). AlphaMissense: likely pathogenic (0.9506); Very rare (popmax 0.00267%, afr).

How common is CPB2 p.Trp264Arg (c.790T>C) in the general population?

CPB2 p.Trp264Arg (c.790T>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CPB2 p.Trp264Arg (c.790T>C)?

AlphaMissense predicts likely pathogenic (score 0.9506) — an in-silico prediction, not a clinical call.

CPB2 p.Trp264Arg

c.790T>C · VCV4233223

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9506 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9506	likely pathogenic · top 5% in CPB2
REVEL	0.647	pathogenic-leaning
SaProt	LLR -8.99	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.59 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2.7, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 51 kb · p 0.00014 · regional, not allelic
Overall
CADD	28.9	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 0.00267% African / African-American · 2/75,036 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000137% 2/1,461,216 alleles · very rare

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.Trp264Arg
Coding: c.790T>C
MANE Select: NM_001872
Type: single nucleotide variant
Location: chr13:46064654 (GRCh38)
Gene constraint: LOEUF 1.373 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.32 · 10 PDB
Residue 264: a disulfide bond; the peptidase m14 domain; a turn

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

Similar variants

CPB2 p.Asp142= Benign ★★ same type
CPB2 p.Tyr245= Likely benign ★★ same type
CPB2 p.Ala22Thr Uncertain significance ★ ⚠ same type
CPB2 p.Ala246Val Uncertain significance ★ ⚠ same type
CPB2 p.Ala340Thr Uncertain significance ★ ⚠ same type
CPB2 p.Ala411Thr Uncertain significance ★ ⚠ same type
CPB2 p.Ala74Thr Uncertain significance ★ ⚠ same type
CPB2 p.Ala7Glu Uncertain significance ★ ⚠ 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/cpb2-p-trp264arg (accessed [today's date]).

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