Is CPOX p.His95Arg (c.284A>G) pathogenic?

CPOX p.His95Arg (c.284A>G) is classified Benign in CPOX (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.069); Low-frequency (popmax 3.01%, afr); Associated with hereditary coproporphyria.

What condition is associated with CPOX p.His95Arg (c.284A>G)?

CPOX p.His95Arg (c.284A>G) is associated with hereditary coproporphyria (ClinVar).

How common is CPOX p.His95Arg (c.284A>G) in the general population?

CPOX p.His95Arg (c.284A>G) is low-frequency (popmax 3.01%, afr) (gnomAD).

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.His95Arg (c.284A>G)?

AlphaMissense predicts likely benign (score 0.069) — an in-silico prediction, not a clinical call.

CPOX p.His95Arg

c.284A>G · rs192332456 · VCV346988

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.069 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.01%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary coproporphyria

Computational evidence

Protein change
AlphaMissense	0.069	likely benign
REVEL	0.457	indeterminate
SaProt	LLR -4.33	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 1.1, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 2,476 bp · p 0.32 · regional, not allelic
Overall
CADD	15.56	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 3.01% African / African-American · 2,241/74,404 alleles

Filtering AF 2.91% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.87%

Overall 0.163% 2,562/1,572,162 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.01%	33
Admixed American	0.262%	382
Remaining individualsnot grpmax-eligible	0.184%	542
Middle Eastern	0.102%	983
European (non-Finnish)	0.00431%	23,200
South Asian	0.0035%	28,538

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.His95Arg
Coding: c.284A>G
MANE Select: NM_000097
dbSNP: rs192332456
Type: single nucleotide variant
Location: chr3:98593221 (GRCh38)
Gene constraint: LOEUF 0.8 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 1 PDB
Residue 95: a UniProt-annotated variant site (in hcp)

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-his95arg (accessed [today's date]).

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