Is CPNE3 p.Gln537Arg (c.1610A>G) pathogenic?

CPNE3 p.Gln537Arg (c.1610A>G) is classified Uncertain significance in CPNE3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: likely benign (0.0899); Ultra-rare (popmax 0.0186%, amr).

How common is CPNE3 p.Gln537Arg (c.1610A>G) in the general population?

CPNE3 p.Gln537Arg (c.1610A>G) is ultra-rare (popmax 0.0186%, amr) (gnomAD).

What do computational predictors say about CPNE3 p.Gln537Arg (c.1610A>G)?

AlphaMissense predicts likely benign (score 0.0899) — an in-silico prediction, not a clinical call.

CPNE3 p.Gln537Arg

c.1610A>G · VCV4233410

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0899 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0186%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0899	likely benign
REVEL	0.011	strongly benign-leaning
SaProt	LLR -6.65	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 -4.6	GERP -4.5
Regional constraint	o/e 1.15	unconstrained · MANE · 30 kb · p 0.0003 · regional, not allelic
Overall
CADD	2.684	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 0.0186% Admixed American · 11/59,174 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00805%

Overall 0.00149% 13/872,874 alleles · ultra-rare exomes 8/720,618 · genomes 5/152,256 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0186%	5,379
Remaining individualsnot grpmax-eligible	0.00525%	19,063

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: CPNE3
Protein: p.Gln537Arg
Coding: c.1610A>G
MANE Select: NM_003909
Type: single nucleotide variant
Location: chr8:86558406 (GRCh38)
Gene constraint: LOEUF 1.389 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.38

Full CPNE3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CPNE3 p.Asn302Ser Uncertain significance ★★ ⚠ same type
CPNE3 p.Ala239Pro Uncertain significance ★ ⚠ same type
CPNE3 p.Ala349Thr Uncertain significance ★ ⚠ same type
CPNE3 p.Ala3Val Uncertain significance ★ ⚠ same type
CPNE3 p.Ala408Thr Uncertain significance ★ ⚠ same type
CPNE3 p.Ala409Thr Uncertain significance ★ ⚠ same type
CPNE3 p.Arg113Gln Uncertain significance ★ ⚠ same type
CPNE3 p.Arg179Gln 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/cpne3-p-gln537arg (accessed [today's date]).

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