Is CPNE7 p.Arg500Pro (c.1499G>C) pathogenic?

CPNE7 p.Arg500Pro (c.1499G>C) is classified Uncertain significance in CPNE7 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-21). AlphaMissense: likely pathogenic (0.9953); Very rare (popmax 0.00834%, amr).

How common is CPNE7 p.Arg500Pro (c.1499G>C) in the general population?

CPNE7 p.Arg500Pro (c.1499G>C) is very rare (popmax 0.00834%, amr) (gnomAD).

What do computational predictors say about CPNE7 p.Arg500Pro (c.1499G>C)?

AlphaMissense predicts likely pathogenic (score 0.9953) — an in-silico prediction, not a clinical call.

CPNE7 p.Arg500Pro

c.1499G>C · rs573409569 · VCV3076794

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9953 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00834%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9953	likely pathogenic · top 4% in CPNE7
REVEL	0.625	indeterminate
SaProt	LLR -16.36	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 2, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 21 kb · p 3e-17 · regional, not allelic
Overall
CADD	26.0	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R575P vs ClinVar R500P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00834% Admixed American · 5/59,966 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00155% 25/1,611,654 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00834%	11,993
European (non-Finnish)	0.00161%	62,066
Remaining individualsnot grpmax-eligible	0.0016%	62,414

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.Arg500Pro
Coding: c.1499G>C
MANE Select: NM_153636
dbSNP: rs573409569
Type: single nucleotide variant
Location: chr16:89595563 (GRCh38)
Gene constraint: LOEUF 1.522 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.41
Residue 500: the vwfa domain

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

Similar variants

CPNE7 p.Arg500Gln Uncertain significance ★ ⚠ same residue
CPNE7 p.Arg500Trp Uncertain significance ★ ⚠ same residue
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

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-arg500pro (accessed [today's date]).

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