Is STAT2 p.Arg148Trp (c.442C>T) pathogenic?

STAT2 p.Arg148Trp (c.442C>T) is classified Pathogenic in STAT2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-07-17). AlphaMissense: likely benign (0.2866); Very rare (popmax 0.00333%, amr); Associated with pseudo-TORCH syndrome 3.

What condition is associated with STAT2 p.Arg148Trp (c.442C>T)?

STAT2 p.Arg148Trp (c.442C>T) is associated with pseudo-TORCH syndrome 3 (ClinVar).

How common is STAT2 p.Arg148Trp (c.442C>T) in the general population?

STAT2 p.Arg148Trp (c.442C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about STAT2 p.Arg148Trp (c.442C>T)?

AlphaMissense predicts likely benign (score 0.2866) — an in-silico prediction, not a clinical call.

STAT2 p.Arg148Trp

c.442C>T · rs1458224681 · VCV973175

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2866 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pseudo-TORCH syndrome 3

Computational evidence

Protein change
AlphaMissense	0.2866	likely benign ⚠ discordant with ClinVar
REVEL	0.265	benign-leaning
SaProt	LLR -9.09	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.3	GERP 1.6, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 13 kb · p 6.2e-18 · regional, not allelic
Overall
CADD	25.7	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 0.00333% Admixed American · 2/60,000 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.00031% 5/1,613,974 alleles · very rare exomes 3/1,461,886 · genomes 2/152,088 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,000
East Asian	0.00223%	44,888
European (non-Finnish)	0.000169%	590,012

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.Arg148Trp
Coding: c.442C>T
MANE Select: NM_005419
dbSNP: rs1458224681
Type: single nucleotide variant
Location: chr12:56355472 (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

Similar variants

STAT2 p.Arg148Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
STAT2 p.Arg667Gln Uncertain significance ★★ ⚠ same condition
STAT2 p.Ser12Gly Uncertain significance ★★ ⚠ same condition
STAT2 p.Arg345Lys Uncertain significance ★ ⚠ same condition
STAT2 p.Arg374Gln Uncertain significance ★ ⚠ same condition
STAT2 p.Arg667Ter Pathogenic/Likely pathogenic ★★ same type
STAT2 p.Gln274Ter Pathogenic/Likely pathogenic ★★ same type
STAT2 p.Ala219Thr Uncertain significance ★★ ⚠ same type

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-arg148trp (accessed [today's date]).

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