Is STAT3 p.Arg278= (c.834T>C) pathogenic?

STAT3 p.Arg278= (c.834T>C) is classified Likely benign in STAT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-06). Ultra-rare (popmax 0.0156%, eas); Associated with STAT3 gain of function.

What condition is associated with STAT3 p.Arg278= (c.834T>C)?

STAT3 p.Arg278= (c.834T>C) is associated with STAT3 gain of function, hyper-IgE recurrent infection syndrome 1, autosomal dominant (ClinVar).

How common is STAT3 p.Arg278= (c.834T>C) in the general population?

STAT3 p.Arg278= (c.834T>C) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

STAT3 p.Arg278=

c.834T>C · rs751849047 · VCV1607603

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Conditions

STAT3 gain of function

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 3.3	GERP -3.7, phastCons 1
Overall
CADD	12.57	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0156% East Asian · 7/44,890 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.000547% 8/1,461,892 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,413
South Asian	0.0011%	91,078

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.Arg278=
Coding: c.834T>C
MANE Select: NM_139276
dbSNP: rs751849047
Type: single nucleotide variant
Location: chr17:42334013 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.80 · 6 PDB
Residue 278: an α-helix; a UniProt-annotated variant site (in admio1; likely pathogenic); a UniProt-annotated variant site (in admio1; likely pathogenic; results in increased transcriptional activation)

Full STAT3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

STAT3 gain of function — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hyper-IgE recurrent infection syndrome 1, autosomal dominant

Similar variants

STAT3 p.Arg278Cys Likely pathogenic ★★ same residue
STAT3 p.Arg278His Pathogenic ★ ⚠ same residue
STAT3 p.Arg278Leu Uncertain significance ★ ⚠ same residue
STAT3 p.Arg152Trp 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

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-arg278 (accessed [today's date]).

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