Is STAT3 p.Thr620Ser (c.1859C>G) pathogenic?

STAT3 p.Thr620Ser (c.1859C>G) is classified Pathogenic in STAT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-17). AlphaMissense: likely pathogenic (0.9671); Absent from gnomAD v4.1; Associated with STAT3 gain of function.

What condition is associated with STAT3 p.Thr620Ser (c.1859C>G)?

STAT3 p.Thr620Ser (c.1859C>G) is associated with STAT3 gain of function, hyper-IgE recurrent infection syndrome 1, autosomal dominant (ClinVar).

How common is STAT3 p.Thr620Ser (c.1859C>G) in the general population?

STAT3 p.Thr620Ser (c.1859C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about STAT3 p.Thr620Ser (c.1859C>G)?

AlphaMissense predicts likely pathogenic (score 0.9671) — an in-silico prediction, not a clinical call.

STAT3 p.Thr620Ser

c.1859C>G · rs1567708034 · VCV1068485

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9671 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

STAT3 gain of function

Computational evidence

Protein change
AlphaMissense	0.9671	likely pathogenic ✓ concordant with ClinVar
REVEL	0.793	moderately pathogenic-leaning
SaProt	LLR -10.21	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.13	constrained · MANE · 716 bp · p 9e-16 · regional, not allelic
Overall
CADD	28.3	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: STAT3
Protein: p.Thr620Ser
Coding: c.1859C>G
MANE Select: NM_139276
dbSNP: rs1567708034
Type: single nucleotide variant
Location: chr17:42323033 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.80 · 6 PDB
Residue 620: a β-strand; the sh2 domain

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.Thr620Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
STAT3 p.Thr620Ala Pathogenic same residue
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

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-thr620ser (accessed [today's date]).

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