Is STAT2 p.Val348Met (c.1042G>A) pathogenic?

STAT2 p.Val348Met (c.1042G>A) is classified Uncertain significance in STAT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-03). AlphaMissense: ambiguous (0.543); Ultra-rare (popmax 0.033%, mid); Associated with primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection.

How common is STAT2 p.Val348Met (c.1042G>A) in the general population?

STAT2 p.Val348Met (c.1042G>A) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about STAT2 p.Val348Met (c.1042G>A)?

AlphaMissense predicts ambiguous (score 0.543) — an in-silico prediction, not a clinical call.

STAT2 p.Val348Met

Q: What condition is associated with STAT2 p.Val348Met (c.1042G>A)?

STAT2 p.Val348Met (c.1042G>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.1042G>A · rs763090413 · VCV1411404

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.543 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.543	ambiguous
REVEL	0.808	moderately pathogenic-leaning
SaProt	LLR -6.70	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 13 kb · p 6.2e-18 · regional, not allelic
Overall
CADD	25.4	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 0.033% Middle Eastern · 2/6,054 alleles

Filtering AF 0.00583% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.000248% 4/1,613,970 alleles · ultra-rare exomes 4/1,461,868 · genomes 0/152,102 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,027
Remaining individualsnot grpmax-eligible	0.0016%	62,500
European (non-Finnish)	8.47e-05%	1,180,002

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.Val348Met
Coding: c.1042G>A
MANE Select: NM_005419
dbSNP: rs763090413
Type: single nucleotide variant
Location: chr12:56350881 (GRCh38)
Gene constraint: LOEUF 0.497 · pLI 0.81 (gnomAD)
Structure: AlphaFold pLDDT 78.45 · 6 PDB
Residue 348: 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-val348met (accessed [today's date]).

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