Is STAT2 p.Lys490fs (c.1467dup) pathogenic?

STAT2 p.Lys490fs (c.1467dup) is classified Pathogenic/Likely pathogenic in STAT2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-19). Very rare (popmax 0.00167%, amr); Associated with primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection.

How common is STAT2 p.Lys490fs (c.1467dup) in the general population?

STAT2 p.Lys490fs (c.1467dup) is very rare (popmax 0.00167%, amr) (gnomAD).

STAT2 p.Lys490fs

Q: What condition is associated with STAT2 p.Lys490fs (c.1467dup)?

STAT2 p.Lys490fs (c.1467dup) 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.1467dup · rs763294380 · VCV1457429

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

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 17 of 24
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.15	GERP -1.8
Overall
CADD	24.2	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 0.00167% Admixed American · 1/59,894 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000496% 8/1,613,152 alleles · very rare exomes 7/1,461,278 · genomes 1/151,874 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,894
European (non-Finnish)	0.000593%	168,526

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.Lys490fs
Coding: c.1467dup
MANE Select: NM_005419
dbSNP: rs763294380
Type: Duplication
Location: chr12:56349032 (GRCh38)
Gene constraint: LOEUF 0.497 · pLI 0.81 (gnomAD)
Structure: AlphaFold pLDDT 78.45 · 6 PDB
Residue 490: the 'mediates interaction with usp18' region; the 'interaction with heartland virus nss' 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.Gly579fs Pathogenic ★ same condition
STAT2 p.Thr226fs 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
STAT2 c.547+14dup 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-lys490fs (accessed [today's date]).

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