Is STAT3 p.Ser701= (c.2103C>T) pathogenic?

STAT3 p.Ser701= (c.2103C>T) is classified Conflicting classifications of pathogenicity in STAT3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-10-28). Very rare (popmax 0.00445%, eas); Associated with hyper-IgE recurrent infection syndrome 1, autosomal dominant.

What condition is associated with STAT3 p.Ser701= (c.2103C>T)?

STAT3 p.Ser701= (c.2103C>T) is associated with hyper-IgE recurrent infection syndrome 1, autosomal dominant (ClinVar).

How common is STAT3 p.Ser701= (c.2103C>T) in the general population?

STAT3 p.Ser701= (c.2103C>T) is very rare (popmax 0.00445%, eas) (gnomAD).

STAT3 p.Ser701=

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.2103C>T · rs1173682056 · VCV2143974

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00445%, 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 4.7	GERP 0.32, phastCons 1
Overall
CADD	13.07	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00445% East Asian · 2/44,894 alleles

Filtering AF 0.00207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00229% 37/1,613,622 alleles · very rare exomes 35/1,461,464 · genomes 2/152,158 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,447
European (non-Finnish)	0.00288%	34,703
South Asian	0.0011%	91,016

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.Ser701=
Coding: c.2103C>T
MANE Select: NM_139276
dbSNP: rs1173682056
Type: single nucleotide variant
Location: chr17:42317223 (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-p-ser701 (accessed [today's date]).

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