Is STAT3 p.Val353Phe (c.1057G>T) pathogenic?

STAT3 p.Val353Phe (c.1057G>T) is classified Pathogenic in STAT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2014-10-30). AlphaMissense: likely pathogenic (0.933); Very rare (popmax 0.00017%, nfe); Associated with STAT3-related early-onset multisystem autoimmune disease.

What condition is associated with STAT3 p.Val353Phe (c.1057G>T)?

STAT3 p.Val353Phe (c.1057G>T) is associated with STAT3-related early-onset multisystem autoimmune disease (ClinVar).

How common is STAT3 p.Val353Phe (c.1057G>T) in the general population?

STAT3 p.Val353Phe (c.1057G>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about STAT3 p.Val353Phe (c.1057G>T)?

AlphaMissense predicts likely pathogenic (score 0.933) — an in-silico prediction, not a clinical call.

STAT3 p.Val353Phe

Q: How is STAT3-related early-onset multisystem autoimmune disease inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1057G>T · rs869312891 · VCV224847

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.933 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

STAT3-related early-onset multisystem autoimmune disease

Computational evidence

Protein change
AlphaMissense	0.933	likely pathogenic ✓ concordant with ClinVar
REVEL	0.982	strongly pathogenic-leaning
SaProt	LLR -8.85	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.39	unconstrained · MANE · 25 kb · p 2.4e-61 · regional, not allelic
Overall
CADD	29.2	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

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,742 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,430 alleles · very rare

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.Val353Phe
Coding: c.1057G>T
MANE Select: NM_139276
dbSNP: rs869312891
Type: single nucleotide variant
Location: chr17:42331524 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.80 · 6 PDB
Residue 353: a β-strand; a UniProt-annotated variant site (in admio1; likely pathogenic)

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

Disease context

STAT3-related early-onset multisystem autoimmune disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For STAT3-related early-onset multisystem autoimmune disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood, Infancy

Similar variants

STAT3 p.Val353= Likely benign ★ same residue
STAT3 p.Arg152Trp Pathogenic ★★ ⚠ same condition
STAT3 p.Arg382Trp Pathogenic ★★ same condition
STAT3 p.Arg423Gln Pathogenic ★★ ⚠ same condition
STAT3 p.Glu415Lys Pathogenic/Likely pathogenic ★★ same condition
STAT3 p.Gly421Arg Pathogenic/Likely pathogenic ★★ ⚠ same condition
STAT3 p.Pro715Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
STAT3 p.Thr716Met 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-val353phe (accessed [today's date]).

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