Is STAT2 p.Thr226fs (c.676dup) pathogenic?

STAT2 p.Thr226fs (c.676dup) is classified Pathogenic in STAT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-01-04). Very rare (popmax 0.00178%, nfe); Associated with primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection.

How common is STAT2 p.Thr226fs (c.676dup) in the general population?

STAT2 p.Thr226fs (c.676dup) is very rare (popmax 0.00178%, nfe) (gnomAD).

STAT2 p.Thr226fs

Q: What condition is associated with STAT2 p.Thr226fs (c.676dup)?

STAT2 p.Thr226fs (c.676dup) 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.676dup · rs2136083409 · VCV1360363

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00178%, nfe)

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	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 24
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00178% European (non-Finnish) · 21/1,180,038 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.0013% 21/1,614,202 alleles · very rare exomes 21/1,461,894 · genomes 0/152,308 · joint denominator

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.Thr226fs
Coding: c.676dup
MANE Select: NM_005419
dbSNP: rs2136083409
Type: Duplication
Location: chr12:56354571 (GRCh38)
Gene constraint: LOEUF 0.497 · pLI 0.81 (gnomAD)
Structure: AlphaFold pLDDT 78.45 · 6 PDB
Residue 226: 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.Thr226= Likely benign ★ same residue
STAT2 p.Lys490fs Pathogenic/Likely pathogenic ★★ same condition
STAT2 p.Gly579fs Pathogenic ★ same condition
STAT2 c.382-9dup Conflicting classifications of pathogenicity ★ same condition
STAT2 c.634-3dup Uncertain significance ★ same condition
STAT2 c.1095-19dup Benign ★ same condition
STAT2 c.2102+9_2102+12dup Likely benign ★ same condition
STAT2 c.471+15dup 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/stat2-p-thr226fs (accessed [today's date]).

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