Is STAT2 p.Asp558Glu (c.1674C>A) pathogenic?

STAT2 p.Asp558Glu (c.1674C>A) is classified Uncertain significance in STAT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-18). AlphaMissense: likely pathogenic (0.6264); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with STAT2 p.Asp558Glu (c.1674C>A)?

STAT2 p.Asp558Glu (c.1674C>A) is associated with Inborn genetic diseases, primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection (ClinVar).

How common is STAT2 p.Asp558Glu (c.1674C>A) in the general population?

STAT2 p.Asp558Glu (c.1674C>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about STAT2 p.Asp558Glu (c.1674C>A)?

AlphaMissense predicts likely pathogenic (score 0.6264) — an in-silico prediction, not a clinical call.

STAT2 p.Asp558Glu

c.1674C>A · rs201603822 · VCV1911619

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6264 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6264	likely pathogenic
REVEL	0.401	indeterminate
SaProt	LLR -6.15	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 0.84, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 13 kb · p 6.2e-18 · regional, not allelic
Overall
CADD	24.6	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 0.00333% Admixed American · 2/59,998 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000372% 6/1,614,086 alleles · very rare exomes 3/1,461,892 · genomes 3/152,194 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,999
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.000254%	393,342

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.Asp558Glu
Coding: c.1674C>A
MANE Select: NM_005419
dbSNP: rs201603822
Type: single nucleotide variant
Location: chr12:56348579 (GRCh38)
Gene constraint: LOEUF 0.497 · pLI 0.81 (gnomAD)
Structure: AlphaFold pLDDT 78.45 · 6 PDB
Residue 558: 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

Inborn genetic diseases — 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-asp558glu (accessed [today's date]).

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