Is CPNE3 p.Pro399Ala (c.1195C>G) pathogenic?

CPNE3 p.Pro399Ala (c.1195C>G) is classified Uncertain significance in CPNE3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-29). AlphaMissense: ambiguous (0.5264); Absent from gnomAD v4.1.

How common is CPNE3 p.Pro399Ala (c.1195C>G) in the general population?

CPNE3 p.Pro399Ala (c.1195C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CPNE3 p.Pro399Ala (c.1195C>G)?

AlphaMissense predicts ambiguous (score 0.5264) — an in-silico prediction, not a clinical call.

CPNE3 p.Pro399Ala

c.1195C>G · VCV3269220

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5264 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.5264	ambiguous
REVEL	0.636	indeterminate
SaProt	LLR -12.68	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.6, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 30 kb · p 0.0003 · regional, not allelic
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CPNE3
Protein: p.Pro399Ala
Coding: c.1195C>G
MANE Select: NM_003909
Type: single nucleotide variant
Location: chr8:86554925 (GRCh38)
Gene constraint: LOEUF 1.389 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.38
Residue 399: the vwfa domain

Full CPNE3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CPNE3 p.Asn302Ser Uncertain significance ★★ ⚠ same type
CPNE3 p.Ala239Pro Uncertain significance ★ ⚠ same type
CPNE3 p.Ala349Thr Uncertain significance ★ ⚠ same type
CPNE3 p.Ala3Val Uncertain significance ★ ⚠ same type
CPNE3 p.Ala408Thr Uncertain significance ★ ⚠ same type
CPNE3 p.Ala409Thr Uncertain significance ★ ⚠ same type
CPNE3 p.Arg113Gln Uncertain significance ★ ⚠ same type
CPNE3 p.Arg179Gln 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/cpne3-p-pro399ala (accessed [today's date]).

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