Is STAT2 p.Leu520Val (c.1558C>G) pathogenic?

STAT2 p.Leu520Val (c.1558C>G) is classified Uncertain significance in STAT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-02-06). AlphaMissense: ambiguous (0.3992); Very rare (popmax 0.00133%, afr); Associated with primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection.

How common is STAT2 p.Leu520Val (c.1558C>G) in the general population?

STAT2 p.Leu520Val (c.1558C>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about STAT2 p.Leu520Val (c.1558C>G)?

AlphaMissense predicts ambiguous (score 0.3992) — an in-silico prediction, not a clinical call.

STAT2 p.Leu520Val

Q: What condition is associated with STAT2 p.Leu520Val (c.1558C>G)?

STAT2 p.Leu520Val (c.1558C>G) 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.1558C>G · rs2136052949 · VCV1053598

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3992 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.3992	ambiguous
REVEL	0.788	moderately pathogenic-leaning
SaProt	LLR -10.97	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	Δ0.95	donor gain · deltas
Pangolin	Δ0.86	gain · loss 0.61 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6.4	GERP -0.24, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 13 kb · p 6.2e-18 · regional, not allelic
Overall
CADD	34.0	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 0.00133% African / African-American · 1/75,048 alleles

Overall 6.2e-05% 1/1,613,490 alleles · very rare exomes 1/1,461,168 · genomes 0/152,322 · joint denominator

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.Leu520Val
Coding: c.1558C>G
MANE Select: NM_005419
dbSNP: rs2136052949
Type: single nucleotide variant
Location: chr12:56348942 (GRCh38)
Gene constraint: LOEUF 0.497 · pLI 0.81 (gnomAD)
Structure: AlphaFold pLDDT 78.45 · 6 PDB
Residue 520: the 'mediates interaction with usp18' region; the 'interaction with heartland virus nss' region; an α-helix

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-leu520val (accessed [today's date]).

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