Is CPNE9 p.Val412Ala (c.1235T>C) pathogenic?

CPNE9 p.Val412Ala (c.1235T>C) is classified Uncertain significance in CPNE9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). AlphaMissense: ambiguous (0.5621); Ultra-rare (popmax 0.0334%, amr).

How common is CPNE9 p.Val412Ala (c.1235T>C) in the general population?

CPNE9 p.Val412Ala (c.1235T>C) is ultra-rare (popmax 0.0334%, amr) (gnomAD).

What do computational predictors say about CPNE9 p.Val412Ala (c.1235T>C)?

AlphaMissense predicts ambiguous (score 0.5621) — an in-silico prediction, not a clinical call.

CPNE9 p.Val412Ala

c.1235T>C · VCV4656214

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5621 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, amr)

Computational evidence

Protein change
AlphaMissense	0.5621	ambiguous
REVEL	0.45	indeterminate
SaProt	LLR -8.92	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.3, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 24 kb · p 1.4e-07 · regional, not allelic
Overall
CADD	27.4	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 0.0334% Admixed American · 20/59,940 alleles

Filtering AF 0.0221% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.00124% 20/1,612,054 alleles · ultra-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.Val412Ala
Coding: c.1235T>C
MANE Select: NM_153635
Type: single nucleotide variant
Location: chr3:9718596 (GRCh38)
Gene constraint: LOEUF 0.863 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.15
Residue 412: the vwfa domain

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

Similar variants

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
CPNE9 p.Arg484Cys 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-val412ala (accessed [today's date]).

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