Is CPOX p.Arg447Cys (c.1339C>T) pathogenic?

CPOX p.Arg447Cys (c.1339C>T) is classified Conflicting classifications of pathogenicity in CPOX (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.1186); Rare (popmax 0.13%, sas); Associated with harderoporphyria.

What condition is associated with CPOX p.Arg447Cys (c.1339C>T)?

CPOX p.Arg447Cys (c.1339C>T) is associated with harderoporphyria, hereditary coproporphyria (ClinVar).

How common is CPOX p.Arg447Cys (c.1339C>T) in the general population?

CPOX p.Arg447Cys (c.1339C>T) is rare (popmax 0.13%, sas) (gnomAD).

How is Harderoporphyria inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CPOX p.Arg447Cys (c.1339C>T)?

AlphaMissense predicts likely benign (score 0.1186) — an in-silico prediction, not a clinical call.

CPOX p.Arg447Cys

c.1339C>T · rs28931603 · VCV459

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1186 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.13%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

harderoporphyria

Computational evidence

Protein change
AlphaMissense	0.1186	likely benign
REVEL	0.856	moderately pathogenic-leaning
SaProt	LLR -10.61	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 10 kb · p 7.6e-05 · regional, not allelic
Overall
CADD	32.0	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 0.13% South Asian · 118/91,090 alleles

Filtering AF 0.11% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.103%

Overall 0.0313% 506/1,614,170 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.219%	456
South Asiangrpmax	0.13%	772
Middle Eastern	0.033%	3,031
European (non-Finnish)	0.0299%	3,343
Remaining individualsnot grpmax-eligible	0.0208%	4,808
Admixed American	0.0117%	8,575
African / African-American	0.00932%	10,725
Finnishnot grpmax-eligible	0.00469%	21,341
East Asian	0.00223%	44,882

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CPOX
Protein: p.Arg447Cys
Coding: c.1339C>T
MANE Select: NM_000097
dbSNP: rs28931603
Type: single nucleotide variant
Location: chr3:98580709 (GRCh38)
Gene constraint: LOEUF 0.8 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 1 PDB
Residue 447: a UniProt-annotated variant site (in hcp); an α-helix

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

Disease context

harderoporphyria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary coproporphyria

For Harderoporphyria (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

CPOX p.Arg447His Uncertain significance ★★ ⚠ same residue
CPOX p.Gln160Ter Pathogenic ★★ same condition
CPOX p.Glu201Lys Pathogenic/Likely pathogenic ★★ same condition
CPOX p.Lys404Glu Pathogenic/Likely pathogenic ★★ same condition
CPOX p.Arg60Gly Uncertain significance ★★ ⚠ same condition
CPOX p.Thr56Met Uncertain significance ★★ ⚠ same condition
CPOX p.Val16Gly Uncertain significance ★★ ⚠ same condition
CPOX c.1172+14A>G Benign ★★ same condition

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/cpox-p-arg447cys (accessed [today's date]).

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