Is STAT6 p.Phe289Tyr (c.866T>A) pathogenic?

STAT6 p.Phe289Tyr (c.866T>A) is classified Uncertain significance in STAT6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-07). AlphaMissense: likely pathogenic (0.8529); Absent from gnomAD v4.1; Associated with hyper-IgE syndrome 6, autosomal dominant, with recurrent infections.

What condition is associated with STAT6 p.Phe289Tyr (c.866T>A)?

STAT6 p.Phe289Tyr (c.866T>A) is associated with hyper-IgE syndrome 6, autosomal dominant, with recurrent infections (ClinVar).

How common is STAT6 p.Phe289Tyr (c.866T>A) in the general population?

STAT6 p.Phe289Tyr (c.866T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about STAT6 p.Phe289Tyr (c.866T>A)?

AlphaMissense predicts likely pathogenic (score 0.8529) — an in-silico prediction, not a clinical call.

STAT6 p.Phe289Tyr

c.866T>A · VCV4291806

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8529 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyper-IgE syndrome 6, autosomal dominant, with recurrent infections

Computational evidence

Protein change
AlphaMissense	0.8529	likely pathogenic
REVEL	0.833	moderately pathogenic-leaning
SaProt	LLR -11.23	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.1	GERP 2.4, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 3,517 bp · p 6e-06 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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: STAT6
Protein: p.Phe289Tyr
Coding: c.866T>A
MANE Select: NM_003153
Type: single nucleotide variant
Location: chr12:57105286 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI 0.56 (gnomAD)
Structure: AlphaFold pLDDT 77.44 · 7 PDB
Residue 289: a β-strand

Full STAT6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hyper-IgE syndrome 6, autosomal dominant, with recurrent infections — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

STAT6 p.Asp419His Likely pathogenic ★ same condition
STAT6 p.Cys762Tyr Uncertain significance ★ ⚠ same condition
STAT6 p.Glu808Gln Uncertain significance ★ ⚠ same condition
STAT6 p.Gly158Ser Uncertain significance ★ ⚠ same condition
STAT6 p.Ser176Asn Likely benign ★ same condition
STAT6 p.Asp419Gly Pathogenic same condition
STAT6 p.Asp419Tyr Pathogenic same condition
STAT6 p.Asp519His 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/stat6-p-phe289tyr (accessed [today's date]).

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