Is STAT3 c.*669C>T pathogenic?

STAT3 c.669C>T is classified Benign in STAT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Low-frequency (popmax 1.87%, afr); Associated with hyper-IgE recurrent infection syndrome 1, autosomal dominant.

What condition is associated with STAT3 c.*669C>T?

STAT3 c.*669C>T is associated with hyper-IgE recurrent infection syndrome 1, autosomal dominant (ClinVar).

How common is STAT3 c.*669C>T in the general population?

STAT3 c.*669C>T is low-frequency (popmax 1.87%, afr) (gnomAD).

STAT3 c.*669C>T

Q: How is Autosomal dominant hyper-IgE syndrome due to STAT3 deficiency inherited?

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

rs138998960 · VCV323233

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

low-frequency (popmax 1.87%, afr)

Conditions

hyper-IgE recurrent infection syndrome 1, autosomal dominant

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 -0.12	GERP -0.41
Overall
CADD	0.825	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.87% African / African-American · 799/42,642 alleles

Filtering AF 1.77% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.72%

Overall 0.471% 870/184,728 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.87%	53
Middle Eastern	0.405%	247
Remaining individualsnot grpmax-eligible	0.405%	247
Admixed American	0.298%	336
European (non-Finnish)	0.00229%	43,604

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
Coding: c.*669C>T
MANE Select: NM_139276
dbSNP: rs138998960
Type: single nucleotide variant
Location: chr17:42315076 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.80 · 6 PDB

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

Disease context

hyper-IgE recurrent infection syndrome 1, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant hyper-IgE syndrome due to STAT3 deficiency (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

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-c-star-669c-t (accessed [today's date]).

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