Is STAT2 p.Met594Ile (c.1782G>C) pathogenic?

STAT2 p.Met594Ile (c.1782G>C) is classified Benign/Likely benign in STAT2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0839); Common (popmax 6.66%, nfe) — 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.Met594Ile (c.1782G>C)?

AlphaMissense predicts likely benign (score 0.0839) — an in-silico prediction, not a clinical call.

STAT2 p.Met594Ile

Q: What condition is associated with STAT2 p.Met594Ile (c.1782G>C)?

STAT2 p.Met594Ile (c.1782G>C) is associated with primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection (ClinVar).

Q: How common is STAT2 p.Met594Ile (c.1782G>C) in the general population?

STAT2 p.Met594Ile (c.1782G>C) is common (popmax 6.66%, nfe) — 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.1782G>C · rs2066807 · VCV403493

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0839 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 6.66%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.0839	likely benign
REVEL	0.36	indeterminate
SaProt	LLR -3.97	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.068	GERP -3.3, phastCons 0.73
Regional constraint	o/e 0.73	unconstrained · MANE · 13 kb · p 6.2e-18 · regional, not allelic
Overall
CADD	0.418	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 6.66% European (non-Finnish) · 78,593/1,180,026 alleles

Filtering AF 6.62% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.61%

Overall 5.82% 93,983/1,614,160 alleles · common exomes 86,991/1,461,874 · genomes 6,992/152,286 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	6.66%	15
Finnishnot grpmax-eligible	5.45%	18
Remaining individualsnot grpmax-eligible	5.4%	19
Admixed American	5.37%	19
Amishnot grpmax-eligible	4.93%	20
East Asian	3.58%	28
Ashkenazi Jewishnot grpmax-eligible	2.39%	42
Middle Eastern	2.39%	42
South Asian	2.22%	45
African / African-American	1.03%	97

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.Met594Ile
Coding: c.1782G>C
MANE Select: NM_005419
dbSNP: rs2066807
Type: single nucleotide variant
Location: chr12:56346898 (GRCh38)
Gene constraint: LOEUF 0.497 · pLI 0.81 (gnomAD)
Structure: AlphaFold pLDDT 78.45 · 6 PDB
Residue 594: the sh2 domain; a UniProt-annotated variant site (in)

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.Met594Val 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-met594ile (accessed [today's date]).

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