Is CPNE7 p.Pro99Ser (c.295C>T) pathogenic?

CPNE7 p.Pro99Ser (c.295C>T) is classified Uncertain significance in CPNE7 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-21). AlphaMissense: likely benign (0.1043); Very rare (popmax 0.00134%, afr).

How common is CPNE7 p.Pro99Ser (c.295C>T) in the general population?

CPNE7 p.Pro99Ser (c.295C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about CPNE7 p.Pro99Ser (c.295C>T)?

AlphaMissense predicts likely benign (score 0.1043) — an in-silico prediction, not a clinical call.

CPNE7 p.Pro99Ser

c.295C>T · rs746189263 · VCV3076796

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1043 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1043	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -5.81	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 0.54	GERP -3, phastCons 0.001
Regional constraint	o/e 1.30	unconstrained · MANE · 21 kb · p 3e-17 · regional, not allelic
Overall
CADD	13.59	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 0.00134% African / African-American · 1/74,820 alleles

Overall 6.92e-05% 1/1,444,952 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: CPNE7
Protein: p.Pro99Ser
Coding: c.295C>T
MANE Select: NM_153636
dbSNP: rs746189263
Type: single nucleotide variant
Location: chr16:89577659 (GRCh38)
Gene constraint: LOEUF 1.522 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.41
Residue 99: the c2 1 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-pro99ser (accessed [today's date]).

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