Is STAT6 p.Asp419His (c.1255G>C) pathogenic?

STAT6 p.Asp419His (c.1255G>C) is classified Likely pathogenic in STAT6 (ClinVar, Single submitter, 3 submitters; last evaluated 2023-10-23). AlphaMissense: likely pathogenic (0.9976); Absent from gnomAD v4.1; Associated with hyper-IgE syndrome 6, autosomal dominant, with recurrent infections.

What condition is associated with STAT6 p.Asp419His (c.1255G>C)?

STAT6 p.Asp419His (c.1255G>C) is associated with hyper-IgE syndrome 6, autosomal dominant, with recurrent infections (ClinVar).

How common is STAT6 p.Asp419His (c.1255G>C) in the general population?

STAT6 p.Asp419His (c.1255G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about STAT6 p.Asp419His (c.1255G>C)?

AlphaMissense predicts likely pathogenic (score 0.9976) — an in-silico prediction, not a clinical call.

STAT6 p.Asp419His

c.1255G>C · rs11172102 · VCV2582689

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9976 · 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	0.9976	likely pathogenic ✓ concordant with ClinVar · top 5% in STAT6
REVEL	0.755	pathogenic-leaning
SaProt	LLR -13.54	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 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 5,635 bp · p 1.9e-12 · regional, not allelic
Overall
CADD	29.3	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: STAT6
Protein: p.Asp419His
Coding: c.1255G>C
MANE Select: NM_003153
dbSNP: rs11172102
Type: single nucleotide variant
Location: chr12:57102879 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI 0.56 (gnomAD)
Structure: AlphaFold pLDDT 77.44 · 7 PDB
Residue 419: a UniProt-annotated variant site (in hies6; likely pathogenic; increased dna-binding transcription factor activity; increased stat6 phosphorylation at baseline and after stimulation with il4); a UniProt-annotated variant site (in hies6; likely pathogenic; gain of function in interleukin-4-mediated signaling pathway; increased dna-binding transcription factor activity; increased stat6 phosphorylation at baseline and after stimulation with il4); a UniProt-annotated variant site (in hies6; likely pathogenic; gain of function in interleukin-4-mediated signaling pathway; increased dna-binding transcription factor activity; increased protein abundance in patient-derived fibroblasts)

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.Asp419Gly Pathogenic same residue
STAT6 p.Asp419Tyr Pathogenic same residue
STAT6 p.Cys762Tyr Uncertain significance ★ ⚠ same condition
STAT6 p.Glu808Gln Uncertain significance ★ ⚠ same condition
STAT6 p.Gly158Ser Uncertain significance ★ ⚠ same condition
STAT6 p.Phe289Tyr Uncertain significance ★ ⚠ same condition
STAT6 p.Ser176Asn Likely benign ★ 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-asp419his (accessed [today's date]).

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