Is CPOX p.Thr76fs (c.225del) pathogenic?

CPOX p.Thr76fs (c.225del) is classified Pathogenic in CPOX (ClinVar, Single submitter, 1 submitter; last evaluated 2018-08-29). Very rare (popmax 8.93e-05%, nfe).

How common is CPOX p.Thr76fs (c.225del) in the general population?

CPOX p.Thr76fs (c.225del) is very rare (popmax 8.93e-05%, nfe) (gnomAD).

CPOX p.Thr76fs

c.225del · rs1576306935 · VCV650602

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.93e-05%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 7
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1	GERP -0.26

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.93e-05% European (non-Finnish) · 1/1,119,468 alleles

Overall 7.58e-05% 1/1,319,138 alleles · very rare

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.Thr76fs
Coding: c.225del
MANE Select: NM_000097
dbSNP: rs1576306935
Type: Deletion
Location: chr3:98593280 (GRCh38)
Gene constraint: LOEUF 0.8 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 1 PDB
Residue 76: a UniProt-annotated variant site (in hcp)

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

Similar variants

CPOX p.Asn213fs Pathogenic ★ same type
CPOX p.Gln221fs Pathogenic ★ same type
CPOX p.Glu216fs Pathogenic ★ same type
CPOX p.Gly11fs Pathogenic ★ same type
CPOX p.Ser177fs Pathogenic ★ same type
CPOX p.Val354fs Likely pathogenic ★ same type
CPOX c.1172+8_1172+11del Uncertain significance ★ same type
CPOX p.Cys164_Val170del Pathogenic 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/cpox-p-thr76fs (accessed [today's date]).

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