Is CPNE3 p.Pro477Ser (c.1429C>T) pathogenic?

CPNE3 p.Pro477Ser (c.1429C>T) is classified Uncertain significance in CPNE3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-04). AlphaMissense: likely benign (0.0863); Ultra-rare (popmax 0.0439%, afr).

How common is CPNE3 p.Pro477Ser (c.1429C>T) in the general population?

CPNE3 p.Pro477Ser (c.1429C>T) is ultra-rare (popmax 0.0439%, afr) (gnomAD).

What do computational predictors say about CPNE3 p.Pro477Ser (c.1429C>T)?

AlphaMissense predicts likely benign (score 0.0863) — an in-silico prediction, not a clinical call.

CPNE3 p.Pro477Ser

c.1429C>T · VCV4656175

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0863 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0439%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0863	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -6.34	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 3.2	GERP 0.59, phastCons 0.28
Regional constraint	o/e 1.15	unconstrained · MANE · 30 kb · p 0.0003 · regional, not allelic
Overall
CADD	16.99	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 0.0439% African / African-American · 27/61,452 alleles

Filtering AF 0.031% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0266%

Overall 0.00309% 27/873,012 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: CPNE3
Protein: p.Pro477Ser
Coding: c.1429C>T
MANE Select: NM_003909
Type: single nucleotide variant
Location: chr8:86556276 (GRCh38)
Gene constraint: LOEUF 1.389 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.38
Residue 477: the vwfa domain

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-pro477ser (accessed [today's date]).

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