Is STAT2 p.Pro488Ala (c.1462C>G) pathogenic?

STAT2 p.Pro488Ala (c.1462C>G) is classified Conflicting classifications of pathogenicity in STAT2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1014); Rare (popmax 0.207%, amr); Associated with Inborn genetic diseases.

What condition is associated with STAT2 p.Pro488Ala (c.1462C>G)?

STAT2 p.Pro488Ala (c.1462C>G) is associated with Inborn genetic diseases, primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection (ClinVar).

How common is STAT2 p.Pro488Ala (c.1462C>G) in the general population?

STAT2 p.Pro488Ala (c.1462C>G) is rare (popmax 0.207%, amr) (gnomAD).

What do computational predictors say about STAT2 p.Pro488Ala (c.1462C>G)?

AlphaMissense predicts likely benign (score 0.1014) — an in-silico prediction, not a clinical call.

STAT2 p.Pro488Ala

c.1462C>G · rs750338004 · VCV769825

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1014 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.207%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1014	likely benign
REVEL	0.369	indeterminate
SaProt	LLR -10.56	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.28	acceptor loss, 9 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 5	GERP 0.79, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 13 kb · p 6.2e-18 · regional, not allelic
Overall
CADD	21.3	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 0.207% Admixed American · 124/59,938 alleles

Filtering AF 0.177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.166%

Overall 0.0102% 165/1,613,402 alleles · rare exomes 151/1,461,242 · genomes 14/152,160 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.207%	483
Remaining individualsnot grpmax-eligible	0.0096%	10,411
European (non-Finnish)	0.0028%	35,749
African / African-American	0.00134%	74,900
South Asian	0.0011%	91,004

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.Pro488Ala
Coding: c.1462C>G
MANE Select: NM_005419
dbSNP: rs750338004
Type: single nucleotide variant
Location: chr12:56349038 (GRCh38)
Gene constraint: LOEUF 0.497 · pLI 0.81 (gnomAD)
Structure: AlphaFold pLDDT 78.45 · 6 PDB
Residue 488: 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.Pro488Leu Uncertain significance ★ ⚠ same residue
STAT2 p.Pro488Ser Uncertain significance ★ ⚠ same residue
STAT2 p.Pro488= Likely benign ★ 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

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-pro488ala (accessed [today's date]).

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