Is STAT2 p.Arg148Gln (c.443G>A) pathogenic?

STAT2 p.Arg148Gln (c.443G>A) is classified Conflicting classifications of pathogenicity in STAT2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-11-04). AlphaMissense: likely benign (0.1858); Very rare (popmax 0.000763%, nfe); Associated with pseudo-TORCH syndrome 3.

What condition is associated with STAT2 p.Arg148Gln (c.443G>A)?

STAT2 p.Arg148Gln (c.443G>A) is associated with pseudo-TORCH syndrome 3, primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection (ClinVar).

How common is STAT2 p.Arg148Gln (c.443G>A) in the general population?

STAT2 p.Arg148Gln (c.443G>A) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about STAT2 p.Arg148Gln (c.443G>A)?

AlphaMissense predicts likely benign (score 0.1858) — an in-silico prediction, not a clinical call.

STAT2 p.Arg148Gln

c.443G>A · rs1879360038 · VCV907069

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1858 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pseudo-TORCH syndrome 3

Computational evidence

Protein change
AlphaMissense	0.1858	likely benign
REVEL	0.246	benign-leaning
SaProt	LLR -5.32	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 13 kb · p 6.2e-18 · regional, not allelic
Overall
CADD	28.8	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 0.000763% European (non-Finnish) · 9/1,180,042 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.00062% 10/1,614,048 alleles · very rare exomes 9/1,461,892 · genomes 1/152,156 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,024
European (non-Finnish)grpmax	0.000763%	131,116

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg148Gln
Coding: c.443G>A
MANE Select: NM_005419
dbSNP: rs1879360038
Type: single nucleotide variant
Location: chr12:56355471 (GRCh38)
Gene constraint: LOEUF 0.497 · pLI 0.81 (gnomAD)
Structure: AlphaFold pLDDT 78.45 · 6 PDB
Residue 148: a UniProt-annotated variant site (in ptorch3; increased cellular sensitivity to type i ifns; fails to appropriately traffic usp18 thereby preventing usp18 to inhibit responses to ifn-i); a UniProt-annotated variant site (in ptorch3; increased cellular sensitivity to type i ifns; loss of interaction with usp18 thereby preventing usp18 to inhibit responses to ifn-i); 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

pseudo-TORCH syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection

Similar variants

STAT2 p.Arg148Trp Pathogenic ⚠ 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-arg148gln (accessed [today's date]).

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