Is STAT3 p.Tyr640Phe (c.1919A>T) pathogenic?

STAT3 p.Tyr640Phe (c.1919A>T) is classified Conflicting classifications of pathogenicity in STAT3 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-11-18). AlphaMissense: ambiguous (0.3677); Very rare (popmax 0.000254%, nfe); Associated with STAT3 gain of function.

What condition is associated with STAT3 p.Tyr640Phe (c.1919A>T)?

STAT3 p.Tyr640Phe (c.1919A>T) is associated with STAT3 gain of function, hyper-IgE recurrent infection syndrome 1, autosomal dominant, diffuse large B-cell lymphoma (ClinVar).

How common is STAT3 p.Tyr640Phe (c.1919A>T) in the general population?

STAT3 p.Tyr640Phe (c.1919A>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about STAT3 p.Tyr640Phe (c.1919A>T)?

AlphaMissense predicts ambiguous (score 0.3677) — an in-silico prediction, not a clinical call.

STAT3 p.Tyr640Phe

c.1919A>T · rs769031989 · VCV372521

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

ambiguous

0.3677 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

STAT3 gain of function

Computational evidence

Protein change
AlphaMissense	0.3677	ambiguous
REVEL	0.644	pathogenic-leaning
SaProt	LLR -7.82	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.13	constrained · MANE · 716 bp · p 9e-16 · regional, not allelic
Overall
CADD	28.9	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 0.000254% European (non-Finnish) · 3/1,179,992 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,036 alleles · very rare exomes 2/1,461,818 · genomes 1/152,218 · joint denominator

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.Tyr640Phe
Coding: c.1919A>T
MANE Select: NM_139276
dbSNP: rs769031989
Type: single nucleotide variant
Location: chr17:42322464 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.80 · 6 PDB
Residue 640: a modified residue (phosphotyrosine; by tyk2); the sh2 domain; a UniProt-annotated variant site (in admio1; likely pathogenic; gain-of-function variant resulting in increased transcriptional activation following ifn and lif stimulation; increased phosphorylation at y-705 and translocation to the nucleus)

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 diffuse large B-cell lymphoma

Similar variants

STAT3 p.Tyr640= Likely benign ★ 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
STAT3 p.Asn466Ser 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-tyr640phe (accessed [today's date]).

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