Is STAT3 p.Asn581= (c.1743C>T) pathogenic?

STAT3 p.Asn581= (c.1743C>T) is classified Benign/Likely benign in STAT3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-01). Rare (popmax 0.128%, sas); Associated with STAT3 gain of function.

What condition is associated with STAT3 p.Asn581= (c.1743C>T)?

STAT3 p.Asn581= (c.1743C>T) is associated with STAT3 gain of function, hyper-IgE recurrent infection syndrome 1, autosomal dominant (ClinVar).

How common is STAT3 p.Asn581= (c.1743C>T) in the general population?

STAT3 p.Asn581= (c.1743C>T) is rare (popmax 0.128%, sas) (gnomAD).

STAT3 p.Asn581=

c.1743C>T · rs1141144 · VCV1170478

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.128%, sas)

Conditions

STAT3 gain of function

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.8	GERP -3.7
Overall
CADD	1.723	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.128% South Asian · 117/91,080 alleles

Filtering AF 0.11% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.102%

Overall 0.011% 177/1,614,168 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.128%	778
Middle Eastern	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.0096%	10,418
European (non-Finnish)	0.00432%	23,138
East Asian	0.00223%	44,892

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: STAT3
Protein: p.Asn581=
Coding: c.1743C>T
MANE Select: NM_139276
dbSNP: rs1141144
Type: single nucleotide variant
Location: chr17:42323265 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.80 · 6 PDB
Residue 581: an α-helix; the sh2 domain

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

Disease context

STAT3 gain of function — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hyper-IgE recurrent infection syndrome 1, autosomal dominant

Similar variants

STAT3 p.Arg152Trp Pathogenic ★★ ⚠ same condition
STAT3 p.Arg278Cys Likely pathogenic ★★ same condition
STAT3 p.Arg335Trp Pathogenic/Likely pathogenic ★★ same condition
STAT3 p.Arg382Gln Pathogenic ★★ same condition
STAT3 p.Arg382Trp Pathogenic ★★ same condition
STAT3 p.Arg423Gln Pathogenic ★★ ⚠ same condition
STAT3 p.Asn466Ser Pathogenic ★★ ⚠ same condition
STAT3 p.Asn466Thr Pathogenic/Likely pathogenic ★★ ⚠ 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-asn581 (accessed [today's date]).

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