Is CPNE2 p.Ser175Leu (c.524C>T) pathogenic?

CPNE2 p.Ser175Leu (c.524C>T) is classified Uncertain significance in CPNE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). AlphaMissense: likely pathogenic (0.9456); Very rare (popmax 8.47e-05%, nfe).

How common is CPNE2 p.Ser175Leu (c.524C>T) in the general population?

CPNE2 p.Ser175Leu (c.524C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CPNE2 p.Ser175Leu (c.524C>T)?

AlphaMissense predicts likely pathogenic (score 0.9456) — an in-silico prediction, not a clinical call.

CPNE2 p.Ser175Leu

c.524C>T · VCV4656167

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9456 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9456	likely pathogenic
REVEL	0.865	moderately pathogenic-leaning
SaProt	LLR -16.68	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 12 kb · p 0.069 · regional, not allelic
Overall
CADD	33.0	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,014 alleles

Overall 6.84e-05% 1/1,461,810 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: CPNE2
Protein: p.Ser175Leu
Coding: c.524C>T
MANE Select: NM_152727
Type: single nucleotide variant
Location: chr16:57119211 (GRCh38)
Gene constraint: LOEUF 0.771 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.76
Residue 175: the c2 2 domain

Full CPNE2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CPNE2 p.Ala12Val Uncertain significance ★ ⚠ same type
CPNE2 p.Ala147Thr Uncertain significance ★ ⚠ same type
CPNE2 p.Ala14Glu Uncertain significance ★ ⚠ same type
CPNE2 p.Ala378Val Uncertain significance ★ ⚠ same type
CPNE2 p.Ala475Gly Uncertain significance ★ ⚠ same type
CPNE2 p.Ala475Val Uncertain significance ★ ⚠ same type
CPNE2 p.Ala478Thr Uncertain significance ★ ⚠ same type
CPNE2 p.Ala548Thr 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/cpne2-p-ser175leu (accessed [today's date]).

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