Is CPE p.Leu474= (c.1422A>G) pathogenic?

CPE p.Leu474= (c.1422A>G) is classified Benign/Likely benign in CPE (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-15). Low-frequency (popmax 1.28%, afr); Associated with BDV syndrome.

What condition is associated with CPE p.Leu474= (c.1422A>G)?

CPE p.Leu474= (c.1422A>G) is associated with BDV syndrome (ClinVar).

How common is CPE p.Leu474= (c.1422A>G) in the general population?

CPE p.Leu474= (c.1422A>G) is low-frequency (popmax 1.28%, afr) (gnomAD).

CPE p.Leu474=

c.1422A>G · rs112824368 · VCV1572366

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.28%, afr)

Conditions

BDV syndrome

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 2.1	GERP -1.9, phastCons 1
Overall
CADD	4.722	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.28% African / African-American · 932/72,730 alleles

Filtering AF 1.21% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.19%

Overall 0.0674% 1,052/1,561,004 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.28%	78
Remaining individualsnot grpmax-eligible	0.101%	989
Admixed American	0.0928%	1,078
Middle Eastern	0.0682%	1,466
South Asian	0.00375%	26,693
European (non-Finnish)	0.000346%	288,860

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.Leu474=
Coding: c.1422A>G
MANE Select: NM_001873
dbSNP: rs112824368
Type: single nucleotide variant
Location: chr4:165497601 (GRCh38)
Gene constraint: LOEUF 0.565 · pLI 0.83 (gnomAD)
Structure: AlphaFold pLDDT 90.83
Residue 474: a UniProt-annotated variant site (in bdvs)

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

Disease context

BDV syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For CPE-related Prader-Willi-like syndrome (Orphanet):

Onset: Childhood, Infancy

Similar variants

CPE p.Arg121Ter Pathogenic ★★ same condition
CPE p.Tyr135Ter Pathogenic same condition
CPE c.505-3dup Benign/Likely benign ★★ same condition
CPE p.Ser333fs Pathogenic ★ same condition
CPE p.Ser404fs Likely pathogenic ★ same condition
CPE p.Glu26fs Pathogenic same condition
CPE p.Arg262Trp Uncertain significance ★★ same type
CPE p.Arg297Trp 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/cpe-p-leu474 (accessed [today's date]).

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