Is CPO p.Arg136Cys (c.406C>T) pathogenic?

CPO p.Arg136Cys (c.406C>T) is classified Uncertain significance in CPO (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-29). AlphaMissense: likely benign (0.2091); Very rare (popmax 0.00556%, sas).

How common is CPO p.Arg136Cys (c.406C>T) in the general population?

CPO p.Arg136Cys (c.406C>T) is very rare (popmax 0.00556%, sas) (gnomAD).

What do computational predictors say about CPO p.Arg136Cys (c.406C>T)?

AlphaMissense predicts likely benign (score 0.2091) — an in-silico prediction, not a clinical call.

CPO p.Arg136Cys

c.406C>T · rs762958017 · VCV2302126

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2091 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00556%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2091	likely benign
REVEL	0.051	moderately benign-leaning
SaProt	LLR -12.15	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.93	GERP -0.62, phastCons 0.029
Regional constraint	o/e 0.90	unconstrained · MANE · 30 kb · p 0.04 · regional, not allelic
Overall
CADD	18.22	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 0.00556% South Asian · 5/89,900 alleles

Filtering AF 0.00213% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00138%

Overall 0.000773% 12/1,552,984 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00556%	17,980
Admixed American	0.00334%	29,936
European (non-Finnish)	0.000445%	224,899

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.Arg136Cys
Coding: c.406C>T
MANE Select: NM_173077
dbSNP: rs762958017
Type: single nucleotide variant
Location: chr2:206959664 (GRCh38)
Gene constraint: LOEUF 1.62 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.28 · 1 PDB
Residue 136: an α-helix; the peptidase m14 domain

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

Similar variants

CPO p.Arg136His Likely benign ★ ⚠ same residue
CPO p.Ala109Thr Uncertain significance ★ ⚠ same type
CPO p.Ala289Ser 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-arg136cys (accessed [today's date]).

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