Is STAT3 p.Arg103= (c.309G>C) pathogenic?

STAT3 p.Arg103= (c.309G>C) is classified Likely benign in STAT3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-03). Ultra-rare (popmax 0.0468%, afr); Associated with hyper-IgE recurrent infection syndrome 1, autosomal dominant.

What condition is associated with STAT3 p.Arg103= (c.309G>C)?

STAT3 p.Arg103= (c.309G>C) is associated with hyper-IgE recurrent infection syndrome 1, autosomal dominant (ClinVar).

How common is STAT3 p.Arg103= (c.309G>C) in the general population?

STAT3 p.Arg103= (c.309G>C) is ultra-rare (popmax 0.0468%, afr) (gnomAD).

STAT3 p.Arg103=

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.309G>C · rs17880940 · VCV717039

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0468%, 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 -2.7	GERP -3.5
Overall
CADD	5.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0468% African / African-American · 35/74,730 alleles

Filtering AF 0.0346% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0304%

Overall 0.00224% 36/1,608,350 alleles · ultra-rare exomes 14/1,456,272 · genomes 22/152,078 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0468%	2,135
Admixed American	0.00167%	59,740

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.Arg103=
Coding: c.309G>C
MANE Select: NM_139276
dbSNP: rs17880940
Type: single nucleotide variant
Location: chr17:42345622 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.80 · 6 PDB
Residue 103: a UniProt-annotated variant site (in admio1; uncertain significance)

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.Arg103Trp Likely pathogenic ★ same residue
STAT3 p.Arg103Leu Uncertain significance ★ ⚠ same residue
STAT3 p.Arg103Gln Likely benign ★ 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

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-arg103 (accessed [today's date]).

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