Is CPNE7 p.Pro332Ser (c.994C>T) pathogenic?

CPNE7 p.Pro332Ser (c.994C>T) is classified Uncertain significance in CPNE7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-22). AlphaMissense: likely pathogenic (0.6099); Ultra-rare (popmax 0.0267%, amr).

How common is CPNE7 p.Pro332Ser (c.994C>T) in the general population?

CPNE7 p.Pro332Ser (c.994C>T) is ultra-rare (popmax 0.0267%, amr) (gnomAD).

What do computational predictors say about CPNE7 p.Pro332Ser (c.994C>T)?

AlphaMissense predicts likely pathogenic (score 0.6099) — an in-silico prediction, not a clinical call.

CPNE7 p.Pro332Ser

c.994C>T · rs751689137 · VCV2348549

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6099 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6099	likely pathogenic
REVEL	0.548	indeterminate
SaProt	LLR -12.80	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 1.9, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 21 kb · p 3e-17 · regional, not allelic
Overall
CADD	24.6	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P407S vs ClinVar P332S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0267% Admixed American · 16/59,990 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.0031% 50/1,613,566 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0267%	3,749
Middle Eastern	0.0164%	6,082
East Asian	0.0111%	8,979
Remaining individualsnot grpmax-eligible	0.0064%	15,621
African / African-American	0.00534%	18,730
South Asian	0.00329%	30,364
European (non-Finnish)	0.00144%	69,411

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: CPNE7
Protein: p.Pro332Ser
Coding: c.994C>T
MANE Select: NM_153636
dbSNP: rs751689137
Type: single nucleotide variant
Location: chr16:89588741 (GRCh38)
Gene constraint: LOEUF 1.522 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.41
Residue 332: the c2 2 domain

Full CPNE7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CPNE7 c.357+1139G>A Uncertain significance ★ ⚠ same type
CPNE7 c.357+1147G>C Uncertain significance ★ ⚠ same type
CPNE7 c.357+1166A>C Uncertain significance ★ ⚠ same type
CPNE7 c.357+1181G>T Uncertain significance ★ ⚠ same type
CPNE7 c.357+1196G>C Uncertain significance ★ ⚠ same type
CPNE7 c.357+1209C>G Uncertain significance ★ ⚠ same type
CPNE7 c.357+1216C>A Uncertain significance ★ ⚠ same type
CPNE7 c.357+1219C>A 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/cpne7-p-pro332ser (accessed [today's date]).

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