Is CPNE7 p.Cys522Arg (c.1564T>C) pathogenic?

CPNE7 p.Cys522Arg (c.1564T>C) is classified Uncertain significance in CPNE7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-07). AlphaMissense: ambiguous (0.4719); Ultra-rare (popmax 0.024%, afr).

How common is CPNE7 p.Cys522Arg (c.1564T>C) in the general population?

CPNE7 p.Cys522Arg (c.1564T>C) is ultra-rare (popmax 0.024%, afr) (gnomAD).

What do computational predictors say about CPNE7 p.Cys522Arg (c.1564T>C)?

AlphaMissense predicts ambiguous (score 0.4719) — an in-silico prediction, not a clinical call.

CPNE7 p.Cys522Arg

c.1564T>C · VCV4006298

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4719 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.024%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4719	ambiguous
REVEL	0.124	moderately benign-leaning
SaProt	LLR -6.67	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.3	GERP -1.5, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 21 kb · p 3e-17 · regional, not allelic
Overall
CADD	20.3	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM C597R vs ClinVar C522R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.024% African / African-American · 18/74,904 alleles

Filtering AF 0.0155% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.00112% 18/1,609,612 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: CPNE7
Protein: p.Cys522Arg
Coding: c.1564T>C
MANE Select: NM_153636
Type: single nucleotide variant
Location: chr16:89596508 (GRCh38)
Gene constraint: LOEUF 1.522 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.41
Residue 522: the vwfa domain

Full CPNE7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CPNE7 c.357+1139G>A Uncertain significance ★ ⚠ same type
CPNE7 c.357+1147G>C Uncertain significance ★ ⚠ same type
CPNE7 c.357+1166A>C Uncertain significance ★ ⚠ same type
CPNE7 c.357+1181G>T Uncertain significance ★ ⚠ same type
CPNE7 c.357+1196G>C Uncertain significance ★ ⚠ same type
CPNE7 c.357+1209C>G Uncertain significance ★ ⚠ same type
CPNE7 c.357+1216C>A Uncertain significance ★ ⚠ same type
CPNE7 c.357+1219C>A 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/cpne7-p-cys522arg (accessed [today's date]).

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