Is CPOX p.Pro422= (c.1266T>A) pathogenic?

CPOX p.Pro422= (c.1266T>A) is classified Likely benign in CPOX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-11). Ultra-rare (popmax 0.0217%, nfe); Associated with hereditary coproporphyria.

What condition is associated with CPOX p.Pro422= (c.1266T>A)?

CPOX p.Pro422= (c.1266T>A) is associated with hereditary coproporphyria (ClinVar).

How common is CPOX p.Pro422= (c.1266T>A) in the general population?

CPOX p.Pro422= (c.1266T>A) is ultra-rare (popmax 0.0217%, nfe) (gnomAD).

How is Hereditary coproporphyria inherited?

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

CPOX p.Pro422=

c.1266T>A · rs563304155 · VCV346973

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, nfe)

Conditions

hereditary coproporphyria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP 1.6, phastCons 1
Overall
CADD	10.04	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0217% European (non-Finnish) · 256/1,178,552 alleles

Filtering AF 0.0195% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0186%

Overall 0.0167% 270/1,612,354 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0217%	4,604
Remaining individualsnot grpmax-eligible	0.00961%	10,405
African / African-American	0.00668%	14,972
Admixed American	0.00333%	29,998
Finnishnot grpmax-eligible	0.00156%	63,994

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.Pro422=
Coding: c.1266T>A
MANE Select: NM_000097
dbSNP: rs563304155
Type: single nucleotide variant
Location: chr3:98581418 (GRCh38)
Gene constraint: LOEUF 0.8 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 1 PDB
Residue 422: a UniProt-annotated variant site (in hcp); the 'important for dimerization' region

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-pro422 (accessed [today's date]).

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