Is STAT2 p.Thr448Met (c.1343C>T) pathogenic?

STAT2 p.Thr448Met (c.1343C>T) is classified Benign/Likely benign in STAT2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1271); Common (popmax 9.44%, amr) — too common for a highly-penetrant pathogenic allele; Associated with primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection.

What do computational predictors say about STAT2 p.Thr448Met (c.1343C>T)?

AlphaMissense predicts likely benign (score 0.1271) — an in-silico prediction, not a clinical call.

STAT2 p.Thr448Met

Q: What condition is associated with STAT2 p.Thr448Met (c.1343C>T)?

STAT2 p.Thr448Met (c.1343C>T) is associated with primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection (ClinVar).

Q: How common is STAT2 p.Thr448Met (c.1343C>T) in the general population?

STAT2 p.Thr448Met (c.1343C>T) is common (popmax 9.44%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.1343C>T · rs2066815 · VCV475688

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1271 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 9.44%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.1271	likely benign
REVEL	0.697	pathogenic-leaning
SaProt	LLR -11.00	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 13 kb · p 6.2e-18 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.44% Admixed American · 5,665/60,024 alleles

Filtering AF 9.23% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.15%

Overall 0.416% 6,717/1,614,200 alleles · common exomes 5,642/1,461,890 · genomes 1,075/152,310 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	9.44%	11
East Asian	0.744%	134
Remaining individualsnot grpmax-eligible	0.475%	210
African / African-American	0.105%	950
Finnishnot grpmax-eligible	0.0297%	3,371
European (non-Finnish)	0.0256%	3,907
South Asian	0.0231%	4,337

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.Thr448Met
Coding: c.1343C>T
MANE Select: NM_005419
dbSNP: rs2066815
Type: single nucleotide variant
Location: chr12:56349260 (GRCh38)
Gene constraint: LOEUF 0.497 · pLI 0.81 (gnomAD)
Structure: AlphaFold pLDDT 78.45 · 6 PDB
Residue 448: a UniProt-annotated variant site (in); 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.Thr448= 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
STAT2 p.Arg409His 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-thr448met (accessed [today's date]).

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