Is CPE p.His248= (c.744T>C) pathogenic?

CPE p.His248= (c.744T>C) is classified Likely benign in CPE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-08). Very rare (popmax 0.00602%, nfe).

How common is CPE p.His248= (c.744T>C) in the general population?

CPE p.His248= (c.744T>C) is very rare (popmax 0.00602%, nfe) (gnomAD).

CPE p.His248=

c.744T>C · rs762207857 · VCV3054110

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00602%, nfe)

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 -20	GERP -4.1
Overall
CADD	0.014	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00602% European (non-Finnish) · 71/1,179,908 alleles

Filtering AF 0.00486% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00447%

Overall 0.00713% 115/1,613,918 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.05%	2,001
Remaining individualsnot grpmax-eligible	0.0112%	8,925
European (non-Finnish)grpmax	0.00602%	16,618
Admixed American	0.005%	19,999
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
East Asian	0.00223%	44,882

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: CPE
Protein: p.His248=
Coding: c.744T>C
MANE Select: NM_001873
dbSNP: rs762207857
Type: single nucleotide variant
Location: chr4:165482313 (GRCh38)
Gene constraint: LOEUF 0.565 · pLI 0.83 (gnomAD)
Structure: AlphaFold pLDDT 90.83
Residue 248: a UniProt-annotated variant site (in bdvs); the peptidase m14 domain; a binding site

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

Similar variants

CPE p.His248Arg Uncertain significance ★ ⚠ same residue
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

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-his248 (accessed [today's date]).

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