Is CPE p.Pro227= (c.681T>C) pathogenic?

CPE p.Pro227= (c.681T>C) is classified Likely benign in CPE (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-05-17). Very rare (popmax 0.00111%, nfe); Associated with CPE-related disorder.

What condition is associated with CPE p.Pro227= (c.681T>C)?

CPE p.Pro227= (c.681T>C) is associated with CPE-related disorder (ClinVar).

How common is CPE p.Pro227= (c.681T>C) in the general population?

CPE p.Pro227= (c.681T>C) is very rare (popmax 0.00111%, nfe) (gnomAD).

CPE p.Pro227=

c.681T>C · VCV3346875

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00111%, nfe)

Conditions

CPE-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -9.6	GERP -4.1
Overall
CADD	0.646	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00111% European (non-Finnish) · 13/1,174,688 alleles

Filtering AF 0.000618% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000476%

Overall 0.000809% 13/1,607,696 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: CPE
Protein: p.Pro227=
Coding: c.681T>C
MANE Select: NM_001873
Type: single nucleotide variant
Location: chr4:165482250 (GRCh38)
Gene constraint: LOEUF 0.565 · pLI 0.83 (gnomAD)
Structure: AlphaFold pLDDT 90.83
Residue 227: a UniProt-annotated variant site (in bdvs); the peptidase m14 domain

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

Disease context

CPE-related disorder

Similar variants

CPE p.Arg121Ter Pathogenic ★★ same condition
CPE c.974-3C>T Uncertain significance ★ same condition
CPE p.Ile415Met Uncertain significance ★ ⚠ same condition
CPE p.Pro30Ala Uncertain significance ★ ⚠ same condition
CPE c.673-2A>G Uncertain significance same condition
CPE p.Ala231Gly Uncertain significance ⚠ same condition
CPE p.Ala266Ser Uncertain significance ⚠ same condition
CPE p.Ala389Val 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/cpe-p-pro227 (accessed [today's date]).

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