Is STAT2 p.Arg374Gln (c.1121G>A) pathogenic?

STAT2 p.Arg374Gln (c.1121G>A) is classified Uncertain significance in STAT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-15). AlphaMissense: likely benign (0.3067); Very rare (popmax 8.48e-05%, nfe); Associated with pseudo-TORCH syndrome 3.

What condition is associated with STAT2 p.Arg374Gln (c.1121G>A)?

STAT2 p.Arg374Gln (c.1121G>A) is associated with pseudo-TORCH syndrome 3, primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection (ClinVar).

How common is STAT2 p.Arg374Gln (c.1121G>A) in the general population?

STAT2 p.Arg374Gln (c.1121G>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about STAT2 p.Arg374Gln (c.1121G>A)?

AlphaMissense predicts likely benign (score 0.3067) — an in-silico prediction, not a clinical call.

STAT2 p.Arg374Gln

c.1121G>A · VCV3575001

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3067 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

pseudo-TORCH syndrome 3

Computational evidence

Protein change
AlphaMissense	0.3067	likely benign
REVEL	0.624	indeterminate
SaProt	LLR -11.60	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.61, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 13 kb · p 6.2e-18 · regional, not allelic
Overall
CADD	32.0	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 8.48e-05% European (non-Finnish) · 1/1,179,120 alleles

Overall 0.000186% 3/1,610,642 alleles · very rare exomes 2/1,459,150 · genomes 1/151,492 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00313%	31,903
European (non-Finnish)grpmax	8.48e-05%	1,179,120

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.Arg374Gln
Coding: c.1121G>A
MANE Select: NM_005419
Type: single nucleotide variant
Location: chr12:56350185 (GRCh38)
Gene constraint: LOEUF 0.497 · pLI 0.81 (gnomAD)
Structure: AlphaFold pLDDT 78.45 · 6 PDB
Residue 374: the 'mediates interaction with usp18' region; the 'interaction with heartland virus nss' region; the 'interaction with sftsv virus nss' 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.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-arg374gln (accessed [today's date]).

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