Is CPE p.Arg42Pro (c.125G>C) pathogenic?

CPE p.Arg42Pro (c.125G>C) is classified Uncertain significance in CPE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-29). AlphaMissense: likely benign (0.1094); Very rare (popmax 0.000171%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CPE p.Arg42Pro (c.125G>C)?

CPE p.Arg42Pro (c.125G>C) is associated with Inborn genetic diseases (ClinVar).

How common is CPE p.Arg42Pro (c.125G>C) in the general population?

CPE p.Arg42Pro (c.125G>C) is very rare (popmax 0.000171%, nfe) (gnomAD).

What do computational predictors say about CPE p.Arg42Pro (c.125G>C)?

AlphaMissense predicts likely benign (score 0.1094) — an in-silico prediction, not a clinical call.

CPE p.Arg42Pro

c.125G>C · VCV4006160

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1094 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000171%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1094	likely benign
REVEL	0.23	benign-leaning
SaProt	LLR -6.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 118 kb · p 0.00025 · regional, not allelic
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000171% European (non-Finnish) · 2/1,171,302 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000126% 2/1,588,418 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.Arg42Pro
Coding: c.125G>C
MANE Select: NM_001873
Type: single nucleotide variant
Location: chr4:165379346 (GRCh38)
Gene constraint: LOEUF 0.565 · pLI 0.83 (gnomAD)
Structure: AlphaFold pLDDT 90.83

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CPE p.Arg262Trp Uncertain significance ★★ ⚠ same condition
CPE p.Arg297Trp Uncertain significance ★★ ⚠ same condition
CPE p.Asp251Gly Uncertain significance ★★ ⚠ same condition
CPE p.Asp304Ala Uncertain significance ★★ ⚠ same condition
CPE p.Trp21Cys Uncertain significance ★★ ⚠ same condition
CPE p.Gln384= Likely benign ★★ same condition
CPE p.Gln384Ter Pathogenic ★ same condition
CPE p.Ala166Thr 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-arg42pro (accessed [today's date]).

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