Is STAT2 p.Pro731Ser (c.2191C>T) pathogenic?

STAT2 p.Pro731Ser (c.2191C>T) is classified Uncertain significance in STAT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-10). AlphaMissense: likely benign (0.0826); Rare (popmax 0.263%, mid); Associated with primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection.

How common is STAT2 p.Pro731Ser (c.2191C>T) in the general population?

STAT2 p.Pro731Ser (c.2191C>T) is rare (popmax 0.263%, mid) (gnomAD).

What do computational predictors say about STAT2 p.Pro731Ser (c.2191C>T)?

AlphaMissense predicts likely benign (score 0.0826) — an in-silico prediction, not a clinical call.

STAT2 p.Pro731Ser

Q: What condition is associated with STAT2 p.Pro731Ser (c.2191C>T)?

STAT2 p.Pro731Ser (c.2191C>T) 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.2191C>T · rs955030312 · VCV650367

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0826 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.263%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.0826	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -7.68	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 0.68	GERP -0.61
Regional constraint	o/e 0.73	unconstrained · MANE · 13 kb · p 6.2e-18 · regional, not allelic
Overall
CADD	8.449	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.263% Middle Eastern · 16/6,082 alleles

Filtering AF 0.165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.134%

Overall 0.00161% 26/1,612,144 alleles · rare exomes 25/1,459,950 · genomes 1/152,194 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.263%	380
Remaining individualsnot grpmax-eligible	0.00801%	12,486
African / African-American	0.00534%	18,718
Admixed American	0.00168%	59,580

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.Pro731Ser
Coding: c.2191C>T
MANE Select: NM_005419
dbSNP: rs955030312
Type: single nucleotide variant
Location: chr12:56344047 (GRCh38)
Gene constraint: LOEUF 0.497 · pLI 0.81 (gnomAD)
Structure: AlphaFold pLDDT 78.45 · 6 PDB

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.Pro731Gln 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-pro731ser (accessed [today's date]).

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