Is STAT3 p.Ile498Val (c.1492A>G) pathogenic?

STAT3 p.Ile498Val (c.1492A>G) is classified Likely benign in STAT3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.0485); Rare (popmax 0.267%, afr); Associated with hyper-IgE recurrent infection syndrome 1, autosomal dominant.

What condition is associated with STAT3 p.Ile498Val (c.1492A>G)?

STAT3 p.Ile498Val (c.1492A>G) is associated with hyper-IgE recurrent infection syndrome 1, autosomal dominant (ClinVar).

How common is STAT3 p.Ile498Val (c.1492A>G) in the general population?

STAT3 p.Ile498Val (c.1492A>G) is rare (popmax 0.267%, afr) (gnomAD).

What do computational predictors say about STAT3 p.Ile498Val (c.1492A>G)?

AlphaMissense predicts likely benign (score 0.0485) — an in-silico prediction, not a clinical call.

STAT3 p.Ile498Val

Q: How is Autosomal dominant hyper-IgE syndrome due to STAT3 deficiency inherited?

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

c.1492A>G · rs146620441 · VCV542785

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0485 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyper-IgE recurrent infection syndrome 1, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.0485	likely benign
REVEL	0.204	benign-leaning
SaProt	LLR -5.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.20	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 6.1	GERP 1.9, phastCons 1
Regional constraint	o/e 0.39	unconstrained · MANE · 25 kb · p 2.4e-61 · regional, not allelic
Overall
CADD	21.3	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

Grpmax group 0.267% African / African-American · 200/75,014 alleles

Filtering AF 0.236% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.225%

Overall 0.0167% 269/1,614,096 alleles · rare exomes 154/1,461,894 · genomes 115/152,202 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.267%	375
Middle Eastern	0.0495%	2,021
Admixed American	0.02%	5,000
Remaining individualsnot grpmax-eligible	0.0192%	5,209
East Asian	0.00669%	14,957
South Asian	0.00329%	30,360
European (non-Finnish)	0.00305%	32,778

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.Ile498Val
Coding: c.1492A>G
MANE Select: NM_139276
dbSNP: rs146620441
Type: single nucleotide variant
Location: chr17:42324819 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.80 · 6 PDB
Residue 498: an α-helix

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

Disease context

hyper-IgE recurrent infection syndrome 1, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant hyper-IgE syndrome due to STAT3 deficiency (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

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
STAT3 p.Asn466Thr Pathogenic/Likely 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-ile498val (accessed [today's date]).

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