Is CPNE9 p.Pro12Arg (c.35C>G) pathogenic?

CPNE9 p.Pro12Arg (c.35C>G) is classified Uncertain significance in CPNE9 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-20). AlphaMissense: likely pathogenic (0.9071); Very rare (popmax 6.87e-05%).

How common is CPNE9 p.Pro12Arg (c.35C>G) in the general population?

CPNE9 p.Pro12Arg (c.35C>G) is very rare (popmax 6.87e-05%) (gnomAD).

What do computational predictors say about CPNE9 p.Pro12Arg (c.35C>G)?

AlphaMissense predicts likely pathogenic (score 0.9071) — an in-silico prediction, not a clinical call.

CPNE9 p.Pro12Arg

c.35C>G · rs1183603710 · VCV3076810

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9071 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.87e-05%)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9071	likely pathogenic
REVEL	0.273	benign-leaning
SaProt	LLR -10.70	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 1.6, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 1,472 bp · p 0.25 · regional, not allelic
Overall
CADD	27.8	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

Grpmax group 6.87e-05%

Overall 6.87e-05% 1/1,456,312 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: CPNE9
Protein: p.Pro12Arg
Coding: c.35C>G
MANE Select: NM_153635
dbSNP: rs1183603710
Type: single nucleotide variant
Location: chr3:9704031 (GRCh38)
Gene constraint: LOEUF 0.863 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.15
Residue 12: the c2 1 domain

Full CPNE9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CPNE9 p.Pro12Leu Uncertain significance ★ ⚠ same residue
CPNE9 p.Arg123Gln Uncertain significance ★ ⚠ same type
CPNE9 p.Arg147Trp Uncertain significance ★ ⚠ same type
CPNE9 p.Arg228Trp Uncertain significance ★ ⚠ same type
CPNE9 p.Arg261Gln Uncertain significance ★ ⚠ same type
CPNE9 p.Arg364Trp Uncertain significance ★ ⚠ same type
CPNE9 p.Arg395His Uncertain significance ★ ⚠ same type
CPNE9 p.Arg478His 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/cpne9-p-pro12arg (accessed [today's date]).

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