Is CPNE5 p.Ala8Pro (c.22G>C) pathogenic?

CPNE5 p.Ala8Pro (c.22G>C) is classified Uncertain significance in CPNE5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-29). AlphaMissense: likely benign (0.1439); Ultra-rare (popmax 0.0134%, amr).

How common is CPNE5 p.Ala8Pro (c.22G>C) in the general population?

CPNE5 p.Ala8Pro (c.22G>C) is ultra-rare (popmax 0.0134%, amr) (gnomAD).

What do computational predictors say about CPNE5 p.Ala8Pro (c.22G>C)?

AlphaMissense predicts likely benign (score 0.1439) — an in-silico prediction, not a clinical call.

CPNE5 p.Ala8Pro

c.22G>C · VCV4006282

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1439 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1439	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -7.26	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 97 kb · p 1e-12 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0134% Admixed American · 7/52,046 alleles

Filtering AF 0.00627% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00448%

Overall 0.000772% 12/1,553,468 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0134%	7,435
Remaining individualsnot grpmax-eligible	0.00333%	30,063
European (non-Finnish)	0.000261%	382,681

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: CPNE5
Protein: p.Ala8Pro
Coding: c.22G>C
MANE Select: NM_020939
Type: single nucleotide variant
Location: chr6:36839356 (GRCh38)
Gene constraint: LOEUF 0.695 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.40
Residue 8: the c2 1 domain

Full CPNE5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CPNE5 p.Ala185Thr Uncertain significance ★ ⚠ same type
CPNE5 p.Ala469Val Uncertain significance ★ ⚠ same type
CPNE5 p.Ala515Asp Uncertain significance ★ ⚠ same type
CPNE5 p.Arg129Cys Uncertain significance ★ ⚠ same type
CPNE5 p.Arg257Gln Uncertain significance ★ ⚠ same type
CPNE5 p.Arg257Trp Uncertain significance ★ ⚠ same type
CPNE5 p.Arg272Gln Uncertain significance ★ ⚠ same type
CPNE5 p.Arg276His 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/cpne5-p-ala8pro (accessed [today's date]).

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