Is STAT2 p.Arg223Ter (c.667C>T) pathogenic?

STAT2 p.Arg223Ter (c.667C>T) is classified Pathogenic in STAT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-23). Very rare (popmax 0.00134%, afr); Associated with primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection.

How common is STAT2 p.Arg223Ter (c.667C>T) in the general population?

STAT2 p.Arg223Ter (c.667C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

STAT2 p.Arg223Ter

Q: What condition is associated with STAT2 p.Arg223Ter (c.667C>T)?

STAT2 p.Arg223Ter (c.667C>T) is associated with primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection (ClinVar).

Q: How is Primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection inherited?

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

c.667C>T · rs1216776022 · VCV1451222

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 24
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 0.67, phastCons 1
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,892 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,614,004 alleles · very rare exomes 4/1,461,892 · genomes 1/152,112 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,892
European (non-Finnish)	0.000339%	295,004

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: STAT2
Protein: p.Arg223Ter
Coding: c.667C>T
MANE Select: NM_005419
dbSNP: rs1216776022
Type: single nucleotide variant
Location: chr12:56354581 (GRCh38)
Gene constraint: LOEUF 0.497 · pLI 0.81 (gnomAD)
Structure: AlphaFold pLDDT 78.45 · 6 PDB
Residue 223: the 'mediates interaction with usp18' region; an α-helix

Full STAT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

STAT2 p.Arg223Gln Uncertain significance ★ ⚠ same residue
STAT2 p.Arg223Leu Uncertain significance ★ ⚠ same residue
STAT2 p.Arg667Ter Pathogenic/Likely pathogenic ★★ same condition
STAT2 p.Gln274Ter Pathogenic/Likely pathogenic ★★ same condition
STAT2 p.Ala219Thr Uncertain significance ★★ ⚠ same condition
STAT2 p.Ala302Thr Uncertain significance ★★ ⚠ same condition
STAT2 p.Arg300Cys Uncertain significance ★★ ⚠ same condition
STAT2 p.Arg330Gln Uncertain significance ★★ ⚠ 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/stat2-p-arg223ter (accessed [today's date]).

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