Is CPNE9 p.Arg69Ser (c.205C>A) pathogenic?

CPNE9 p.Arg69Ser (c.205C>A) is classified Uncertain significance in CPNE9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-04). AlphaMissense: likely pathogenic (0.7542); Very rare (popmax 0.00267%, afr).

How common is CPNE9 p.Arg69Ser (c.205C>A) in the general population?

CPNE9 p.Arg69Ser (c.205C>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CPNE9 p.Arg69Ser (c.205C>A)?

AlphaMissense predicts likely pathogenic (score 0.7542) — an in-silico prediction, not a clinical call.

CPNE9 p.Arg69Ser

c.205C>A · VCV4656219

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7542 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7542	likely pathogenic
REVEL	0.368	indeterminate
SaProt	LLR -13.49	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.22	donor gain · deltas
Constraint at this position
Conservation	phyloP 7.4	GERP 1.7, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 1,472 bp · p 0.25 · regional, not allelic
Overall
CADD	29.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,892 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00131% 2/152,156 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.Arg69Ser
Coding: c.205C>A
MANE Select: NM_153635
Type: single nucleotide variant
Location: chr3:9704939 (GRCh38)
Gene constraint: LOEUF 0.863 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.15
Residue 69: the c2 1 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-arg69ser (accessed [today's date]).

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