Is CPE p.His267= (c.801C>T) pathogenic?

CPE p.His267= (c.801C>T) is classified Benign/Likely benign in CPE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-04). Common (popmax 13.2%, eas) — too common for a highly-penetrant pathogenic allele.

CPE p.His267=

Q: How common is CPE p.His267= (c.801C>T) in the general population?

CPE p.His267= (c.801C>T) is common (popmax 13.2%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.801C>T · rs4690821 · VCV1599126

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 13.2%, eas) — too common for a highly-penetrant pathogenic allele

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 -4.8	GERP -3.7
Overall
CADD	6.786	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 13.2% East Asian · 5,917/44,848 alleles

Filtering AF 12.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.8%

Overall 5.82% 93,938/1,613,434 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	13.2%	8
Finnishnot grpmax-eligible	9.14%	11
European (non-Finnish)	5.92%	17
Remaining individualsnot grpmax-eligible	5.56%	18
South Asian	5.22%	19
Admixed American	4.54%	22
Ashkenazi Jewishnot grpmax-eligible	1.33%	75
African / African-American	1.17%	85
Middle Eastern	1.06%	95
Amishnot grpmax-eligible	0.768%	130

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.His267=
Coding: c.801C>T
MANE Select: NM_001873
dbSNP: rs4690821
Type: single nucleotide variant
Location: chr4:165484432 (GRCh38)
Gene constraint: LOEUF 0.565 · pLI 0.83 (gnomAD)
Structure: AlphaFold pLDDT 90.83
Residue 267: 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

Similar variants

CPE p.Arg121Ter Pathogenic ★★ same type
CPE p.Arg262Trp Uncertain significance ★★ ⚠ same type
CPE p.Arg297Trp Uncertain significance ★★ ⚠ same type
CPE p.Asp251Gly Uncertain significance ★★ ⚠ same type
CPE p.Asp304Ala Uncertain significance ★★ ⚠ same type
CPE p.Trp21Cys Uncertain significance ★★ ⚠ same type
CPE c.307+13C>T Likely benign ★★ same type
CPE c.672+11C>T Likely benign ★★ 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/cpe-p-his267 (accessed [today's date]).

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