Is STAT3 p.Ile217Phe (c.649A>T) pathogenic?

STAT3 p.Ile217Phe (c.649A>T) is classified Uncertain significance in STAT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-21). AlphaMissense: ambiguous (0.4239); Absent from gnomAD v4.1; Associated with hyper-IgE recurrent infection syndrome 1, autosomal dominant.

What condition is associated with STAT3 p.Ile217Phe (c.649A>T)?

STAT3 p.Ile217Phe (c.649A>T) is associated with hyper-IgE recurrent infection syndrome 1, autosomal dominant (ClinVar).

How common is STAT3 p.Ile217Phe (c.649A>T) in the general population?

STAT3 p.Ile217Phe (c.649A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about STAT3 p.Ile217Phe (c.649A>T)?

AlphaMissense predicts ambiguous (score 0.4239) — an in-silico prediction, not a clinical call.

STAT3 p.Ile217Phe

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.649A>T · rs2509433353 · VCV2044185

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4239 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hyper-IgE recurrent infection syndrome 1, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.4239	ambiguous
REVEL	0.517	indeterminate
SaProt	LLR -8.22	tolerated
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.39	unconstrained · MANE · 25 kb · p 2.4e-61 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: STAT3
Protein: p.Ile217Phe
Coding: c.649A>T
dbSNP: rs2509433353
Type: single nucleotide variant
Location: chr17:42337583 (GRCh38)

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)

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-ile217phe (accessed [today's date]).

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