Is STAT3 p.Pro330= (c.990C>T) pathogenic?

STAT3 p.Pro330= (c.990C>T) is classified Likely benign in STAT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-08-05). Very rare (popmax 0.00223%, eas); Associated with hyper-IgE recurrent infection syndrome 1, autosomal dominant.

What condition is associated with STAT3 p.Pro330= (c.990C>T)?

STAT3 p.Pro330= (c.990C>T) is associated with hyper-IgE recurrent infection syndrome 1, autosomal dominant (ClinVar).

How common is STAT3 p.Pro330= (c.990C>T) in the general population?

STAT3 p.Pro330= (c.990C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

STAT3 p.Pro330=

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.

c.990C>T · rs1278437970 · VCV1139892

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

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 0.28	GERP -2.6, phastCons 0.17
Overall
CADD	9.755	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,896 alleles

Overall 0.000657% 1/152,178 alleles · very rare

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.Pro330=
Coding: c.990C>T
MANE Select: NM_139276
dbSNP: rs1278437970
Type: single nucleotide variant
Location: chr17:42333732 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.80 · 6 PDB
Residue 330: a UniProt-annotated variant site (in admio1; increases transcriptional activity; increases binding to isl1 promoter region; decreases glucose stimulated insulin secretion)

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.Pro330Ser Pathogenic ★ same residue
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

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-pro330 (accessed [today's date]).

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