Is CPNE9 p.Ser448Arg (c.1342A>C) pathogenic?

CPNE9 p.Ser448Arg (c.1342A>C) is classified Uncertain significance in CPNE9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-22). AlphaMissense: likely pathogenic (0.5809); Very rare (popmax 0.00407%, afr).

How common is CPNE9 p.Ser448Arg (c.1342A>C) in the general population?

CPNE9 p.Ser448Arg (c.1342A>C) is very rare (popmax 0.00407%, afr) (gnomAD).

What do computational predictors say about CPNE9 p.Ser448Arg (c.1342A>C)?

AlphaMissense predicts likely pathogenic (score 0.5809) — an in-silico prediction, not a clinical call.

CPNE9 p.Ser448Arg

c.1342A>C · VCV4656213

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5809 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00407%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5809	likely pathogenic
REVEL	0.189	benign-leaning
SaProt	LLR -2.87	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 24 kb · p 1.4e-07 · regional, not allelic
Overall
CADD	24.2	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 0.00407% African / African-American · 3/73,766 alleles

Filtering AF 0.00108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000656%

Overall 0.00119% 19/1,594,812 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00407%	24,589
European (non-Finnish)	0.00137%	73,043

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.Ser448Arg
Coding: c.1342A>C
MANE Select: NM_153635
Type: single nucleotide variant
Location: chr3:9726049 (GRCh38)
Gene constraint: LOEUF 0.863 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.15
Residue 448: 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-ser448arg (accessed [today's date]).

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