Is CPO p.Pro97Leu (c.290C>T) pathogenic?

CPO p.Pro97Leu (c.290C>T) is classified Uncertain significance in CPO (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-06). AlphaMissense: likely benign (0.1183); Very rare (popmax 8.54e-05%, nfe).

How common is CPO p.Pro97Leu (c.290C>T) in the general population?

CPO p.Pro97Leu (c.290C>T) is very rare (popmax 8.54e-05%, nfe) (gnomAD).

What do computational predictors say about CPO p.Pro97Leu (c.290C>T)?

AlphaMissense predicts likely benign (score 0.1183) — an in-silico prediction, not a clinical call.

CPO p.Pro97Leu

c.290C>T · rs766185646 · VCV2310255

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1183 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.54e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1183	likely benign
REVEL	0.045	moderately benign-leaning
SaProt	LLR -8.77	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 0.13	GERP 0.19
Regional constraint	o/e 0.90	unconstrained · MANE · 30 kb · p 0.04 · regional, not allelic
Overall
CADD	12.19	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 8.54e-05% European (non-Finnish) · 1/1,170,350 alleles

Overall 6.93e-05% 1/1,442,726 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: CPO
Protein: p.Pro97Leu
Coding: c.290C>T
MANE Select: NM_173077
dbSNP: rs766185646
Type: single nucleotide variant
Location: chr2:206958323 (GRCh38)
Gene constraint: LOEUF 1.62 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.28 · 1 PDB
Residue 97: the peptidase m14 domain

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

Similar variants

CPO p.Ala109Thr Uncertain significance ★ ⚠ same type
CPO p.Ala289Ser Uncertain significance ★ ⚠ same type
CPO p.Arg136Cys Uncertain significance ★ ⚠ same type
CPO p.Arg169Cys Uncertain significance ★ ⚠ same type
CPO p.Arg299Gln Uncertain significance ★ ⚠ same type
CPO p.Asn183His Uncertain significance ★ ⚠ same type
CPO p.Asn187Asp Uncertain significance ★ ⚠ same type
CPO p.Asn255Thr 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/cpo-p-pro97leu (accessed [today's date]).

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