Is CPOX p.Arg352Cys (c.1054C>T) pathogenic?

CPOX p.Arg352Cys (c.1054C>T) is classified Benign in CPOX (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0694); Common (popmax 13%, afr) — too common for a highly-penetrant pathogenic allele; Associated with hereditary coproporphyria.

What condition is associated with CPOX p.Arg352Cys (c.1054C>T)?

CPOX p.Arg352Cys (c.1054C>T) is associated with hereditary coproporphyria (ClinVar).

How is Hereditary coproporphyria inherited?

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

What do computational predictors say about CPOX p.Arg352Cys (c.1054C>T)?

AlphaMissense predicts likely benign (score 0.0694) — an in-silico prediction, not a clinical call.

CPOX p.Arg352Cys

Q: How common is CPOX p.Arg352Cys (c.1054C>T) in the general population?

CPOX p.Arg352Cys (c.1054C>T) is common (popmax 13%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1054C>T · rs11921054 · VCV346976

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0694 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 13%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary coproporphyria

Computational evidence

Protein change
AlphaMissense	0.0694	likely benign
REVEL	0.186	benign-leaning
SaProt	LLR -7.65	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 -0.2	GERP -2.4
Regional constraint	o/e 0.76	unconstrained · MANE · 10 kb · p 7.6e-05 · regional, not allelic
Overall
CADD	17.96	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 13% African / African-American · 9,769/74,948 alleles

Filtering AF 12.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.7%

Overall 1.9% 30,663/1,614,000 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	13%	8
Ashkenazi Jewishnot grpmax-eligible	4.16%	24
Middle Eastern	3.07%	33
Remaining individualsnot grpmax-eligible	2.62%	38
Admixed American	2.33%	43
South Asian	1.89%	53
European (non-Finnish)	1.18%	85
Finnishnot grpmax-eligible	1.1%	91
East Asian	0.187%	534

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.Arg352Cys
Coding: c.1054C>T
MANE Select: NM_000097
dbSNP: rs11921054
Type: single nucleotide variant
Location: chr3:98585559 (GRCh38)
Gene constraint: LOEUF 0.8 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 1 PDB
Residue 352: a UniProt-annotated variant site (in hcp); a UniProt-annotated variant site (in); an α-helix

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

Disease context

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

For Hereditary coproporphyria (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

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
CPOX c.556+9G>A Benign/Likely 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-arg352cys (accessed [today's date]).

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