Is CPE p.His152= (c.456C>T) pathogenic?

CPE p.His152= (c.456C>T) is classified Likely benign in CPE (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-03-27). Very rare (popmax 0.000254%, nfe); Associated with CPE-related disorder.

What condition is associated with CPE p.His152= (c.456C>T)?

CPE p.His152= (c.456C>T) is associated with CPE-related disorder (ClinVar).

How common is CPE p.His152= (c.456C>T) in the general population?

CPE p.His152= (c.456C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

CPE p.His152=

c.456C>T · VCV3352687

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000254%, 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 0.1	GERP -0.66, phastCons 0.93
Overall
CADD	7.39	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,670 alleles

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

Overall 0.000248% 4/1,613,498 alleles · very rare exomes 4/1,461,178 · genomes 0/152,320 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)grpmax	0.000254%	393,224

Remaining individuals 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: CPE
Protein: p.His152=
Coding: c.456C>T
MANE Select: NM_001873
Type: single nucleotide variant
Location: chr4:165464538 (GRCh38)
Gene constraint: LOEUF 0.565 · pLI 0.83 (gnomAD)
Structure: AlphaFold pLDDT 90.83
Residue 152: 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-his152 (accessed [today's date]).

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