Is CPNE4 p.Pro73Ser (c.217C>T) pathogenic?

CPNE4 p.Pro73Ser (c.217C>T) is classified Uncertain significance in CPNE4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-25). AlphaMissense: likely pathogenic (0.9812); Absent from gnomAD v4.1.

How common is CPNE4 p.Pro73Ser (c.217C>T) in the general population?

CPNE4 p.Pro73Ser (c.217C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CPNE4 p.Pro73Ser (c.217C>T)?

AlphaMissense predicts likely pathogenic (score 0.9812) — an in-silico prediction, not a clinical call.

CPNE4 p.Pro73Ser

c.217C>T · VCV4656186

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9812 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9812	likely pathogenic
REVEL	0.917	moderately pathogenic-leaning
SaProt	LLR -16.00	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 209 kb · p 0.02 · regional, not allelic
Overall
CADD	31.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CPNE4
Protein: p.Pro73Ser
Coding: c.217C>T
MANE Select: NM_130808
Type: single nucleotide variant
Location: chr3:131723589 (GRCh38)
Gene constraint: LOEUF 0.54 · pLI 0.88 (gnomAD)
Structure: AlphaFold pLDDT 87.42
Residue 73: the c2 1 domain

Full CPNE4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CPNE4 p.Ala11Thr Uncertain significance ★ ⚠ same type
CPNE4 p.Arg225Gly Uncertain significance ★ ⚠ same type
CPNE4 p.Arg68His Uncertain significance ★ ⚠ same type
CPNE4 p.Arg90His Uncertain significance ★ ⚠ same type
CPNE4 p.Arg92Gln Uncertain significance ★ ⚠ same type
CPNE4 p.Asn153Ser Uncertain significance ★ ⚠ same type
CPNE4 p.Asn162Ser Uncertain significance ★ ⚠ same type
CPNE4 p.Asp109Asn 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/cpne4-p-pro73ser (accessed [today's date]).

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