Is STAT2 p.Leu442= (c.1326G>A) pathogenic?

STAT2 p.Leu442= (c.1326G>A) is classified Benign/Likely benign in STAT2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-15). Rare (popmax 0.579%, sas); Associated with primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection.

How common is STAT2 p.Leu442= (c.1326G>A) in the general population?

STAT2 p.Leu442= (c.1326G>A) is rare (popmax 0.579%, sas) (gnomAD).

STAT2 p.Leu442=

Q: What condition is associated with STAT2 p.Leu442= (c.1326G>A)?

STAT2 p.Leu442= (c.1326G>A) 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.1326G>A · rs529406351 · VCV542352

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.579%, sas)

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.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.8	GERP -1.7, phastCons 1
Overall
CADD	10.57	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.579% South Asian · 527/91,072 alleles

Filtering AF 0.538% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.522%

Overall 0.0358% 578/1,614,220 alleles · rare exomes 542/1,461,894 · genomes 36/152,326 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.579%	173
Middle Eastern	0.247%	404
Remaining individualsnot grpmax-eligible	0.0496%	2,016
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Admixed American	0.00333%	30,014
East Asian	0.00223%	44,886
European (non-Finnish)	8.47e-05%	1,180,048

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.Leu442=
Coding: c.1326G>A
MANE Select: NM_005419
dbSNP: rs529406351
Type: single nucleotide variant
Location: chr12:56349441 (GRCh38)
Gene constraint: LOEUF 0.497 · pLI 0.81 (gnomAD)
Structure: AlphaFold pLDDT 78.45 · 6 PDB
Residue 442: the 'mediates interaction with usp18' region; the 'interaction with heartland virus nss' region; the 'interaction with sftsv virus nss' region; a β-strand

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.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
STAT2 p.Arg409His Uncertain significance ★★ ⚠ same condition
STAT2 p.Arg510Gln 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-leu442 (accessed [today's date]).

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