Is CPNE2 p.Phe407Val (c.1219T>G) pathogenic?

CPNE2 p.Phe407Val (c.1219T>G) is classified Uncertain significance in CPNE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-11). AlphaMissense: likely pathogenic (0.9745); Ultra-rare (popmax 0.0142%, nfe).

How common is CPNE2 p.Phe407Val (c.1219T>G) in the general population?

CPNE2 p.Phe407Val (c.1219T>G) is ultra-rare (popmax 0.0142%, nfe) (gnomAD).

What do computational predictors say about CPNE2 p.Phe407Val (c.1219T>G)?

AlphaMissense predicts likely pathogenic (score 0.9745) — an in-silico prediction, not a clinical call.

CPNE2 p.Phe407Val

c.1219T>G · VCV4006262

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9745 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0142%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9745	likely pathogenic
REVEL	0.263	benign-leaning
SaProt	LLR -9.78	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 0.46, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 20 kb · p 2.3e-05 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0142% European (non-Finnish) · 168/1,180,048 alleles

Filtering AF 0.0125% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0118%

Overall 0.0108% 175/1,614,126 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0142%	7,024
Remaining individualsnot grpmax-eligible	0.0096%	10,414
African / African-American	0.00133%	74,944

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.Phe407Val
Coding: c.1219T>G
MANE Select: NM_152727
Type: single nucleotide variant
Location: chr16:57137199 (GRCh38)
Gene constraint: LOEUF 0.771 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.76
Residue 407: the vwfa 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-phe407val (accessed [today's date]).

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