Is STAT3 p.Lys392Arg (c.1175A>G) pathogenic?

STAT3 p.Lys392Arg (c.1175A>G) is classified Pathogenic in STAT3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2014-08-01). AlphaMissense: likely pathogenic (0.5857); Absent from gnomAD v4.1; Associated with STAT3-related early-onset multisystem autoimmune disease.

What condition is associated with STAT3 p.Lys392Arg (c.1175A>G)?

STAT3 p.Lys392Arg (c.1175A>G) is associated with STAT3-related early-onset multisystem autoimmune disease (ClinVar).

How common is STAT3 p.Lys392Arg (c.1175A>G) in the general population?

STAT3 p.Lys392Arg (c.1175A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about STAT3 p.Lys392Arg (c.1175A>G)?

AlphaMissense predicts likely pathogenic (score 0.5857) — an in-silico prediction, not a clinical call.

STAT3 p.Lys392Arg

Q: How is STAT3-related early-onset multisystem autoimmune disease inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1175A>G · rs587777648 · VCV144030

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5857 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

STAT3-related early-onset multisystem autoimmune disease

Computational evidence

Protein change
AlphaMissense	0.5857	likely pathogenic ✓ concordant with ClinVar
REVEL	0.911	moderately pathogenic-leaning
SaProt	LLR -8.86	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.39	unconstrained · MANE · 25 kb · p 2.4e-61 · regional, not allelic
Overall
CADD	28.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: STAT3
Protein: p.Lys392Arg
Coding: c.1175A>G
MANE Select: NM_139276
dbSNP: rs587777648
Type: single nucleotide variant
Location: chr17:42329612 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.80 · 6 PDB
Residue 392: a β-strand; a UniProt-annotated variant site (in admio1; results in increased transcriptional activation)

Full STAT3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

STAT3-related early-onset multisystem autoimmune disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For STAT3-related early-onset multisystem autoimmune disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood, Infancy

Similar variants

STAT3 p.Arg152Trp Pathogenic ★★ ⚠ same condition
STAT3 p.Arg382Trp Pathogenic ★★ same condition
STAT3 p.Arg423Gln Pathogenic ★★ ⚠ same condition
STAT3 p.Glu415Lys Pathogenic/Likely pathogenic ★★ same condition
STAT3 p.Gly421Arg Pathogenic/Likely pathogenic ★★ ⚠ same condition
STAT3 p.Pro715Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
STAT3 p.Thr716Met Pathogenic ★★ ⚠ same condition
STAT3 p.Gln117Arg 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/stat3-p-lys392arg (accessed [today's date]).

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