Is CPNE4 p.Ala424= (c.1272G>A) pathogenic?

CPNE4 p.Ala424= (c.1272G>A) is classified Likely benign in CPNE4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). Rare (popmax 0.163%, afr).

How common is CPNE4 p.Ala424= (c.1272G>A) in the general population?

CPNE4 p.Ala424= (c.1272G>A) is rare (popmax 0.163%, afr) (gnomAD).

CPNE4 p.Ala424=

c.1272G>A · VCV4233420

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.163%, afr)

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 -13	GERP -4.7
Overall
CADD	0.204	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.163% African / African-American · 122/74,954 alleles

Filtering AF 0.139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.13%

Overall 0.00899% 145/1,613,144 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.163%	614
Remaining individualsnot grpmax-eligible	0.0112%	8,919
Admixed American	0.01%	9,991
Finnishnot grpmax-eligible	0.00156%	64,018
European (non-Finnish)	0.000763%	131,044

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: CPNE4
Protein: p.Ala424=
Coding: c.1272G>A
MANE Select: NM_130808
Type: single nucleotide variant
Location: chr3:131549977 (GRCh38)
Gene constraint: LOEUF 0.54 · pLI 0.88 (gnomAD)
Structure: AlphaFold pLDDT 87.42
Residue 424: the vwfa domain

Full CPNE4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CPNE4 p.Ala11Thr Uncertain significance ★ ⚠ same type
CPNE4 p.Arg225Gly Uncertain significance ★ ⚠ same type
CPNE4 p.Arg68His Uncertain significance ★ ⚠ same type
CPNE4 p.Arg90His Uncertain significance ★ ⚠ same type
CPNE4 p.Arg92Gln Uncertain significance ★ ⚠ same type
CPNE4 p.Asn153Ser Uncertain significance ★ ⚠ same type
CPNE4 p.Asn162Ser Uncertain significance ★ ⚠ same type
CPNE4 p.Asp109Asn 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/cpne4-p-ala424 (accessed [today's date]).

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