Is STAT4 p.Thr446Ile (c.1337C>T) pathogenic?

STAT4 p.Thr446Ile (c.1337C>T) is classified Conflicting classifications of pathogenicity in STAT4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-05-01). AlphaMissense: ambiguous (0.3884); Rare (popmax 0.11%, nfe); Associated with STAT4-related disorder.

What condition is associated with STAT4 p.Thr446Ile (c.1337C>T)?

STAT4 p.Thr446Ile (c.1337C>T) is associated with STAT4-related disorder (ClinVar).

How common is STAT4 p.Thr446Ile (c.1337C>T) in the general population?

STAT4 p.Thr446Ile (c.1337C>T) is rare (popmax 0.11%, nfe) (gnomAD).

What do computational predictors say about STAT4 p.Thr446Ile (c.1337C>T)?

AlphaMissense predicts ambiguous (score 0.3884) — an in-silico prediction, not a clinical call.

STAT4 p.Thr446Ile

c.1337C>T · rs141331848 · VCV1423453

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3884 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.11%, nfe)

Conditions

STAT4-related disorder

Computational evidence

Protein change
AlphaMissense	0.3884	ambiguous
REVEL	0.589	indeterminate
SaProt	LLR -8.28	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.42 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 114 kb · p 8.5e-09 · regional, not allelic
Overall
CADD	31.0	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 0.11% European (non-Finnish) · 1,300/1,179,904 alleles

Filtering AF 0.105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.103%

Overall 0.091% 1,468/1,614,044 alleles · rare exomes 1,352/1,461,766 · genomes 116/152,278 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.128%	781
European (non-Finnish)grpmax	0.11%	908
Remaining individualsnot grpmax-eligible	0.0672%	1,488
Admixed American	0.02%	5,002
African / African-American	0.0187%	5,361
South Asian	0.0176%	5,692
Ashkenazi Jewishnot grpmax-eligible	0.00675%	14,804

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: STAT4
Protein: p.Thr446Ile
Coding: c.1337C>T
MANE Select: NM_003151
dbSNP: rs141331848
Type: single nucleotide variant
Location: chr2:191039296 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.93 (gnomAD)
Structure: AlphaFold pLDDT 86.87

Full STAT4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

STAT4-related disorder

Similar variants

STAT4 p.Thr446= Benign/Likely benign ★★ same residue
STAT4 p.Phe340Leu Uncertain significance ★★ ⚠ same condition
STAT4 p.Gly618Glu Uncertain significance ★ ⚠ same condition
STAT4 p.Ala245Thr Uncertain significance ★★ ⚠ same type
STAT4 p.Arg241Gln Uncertain significance ★★ ⚠ same type
STAT4 p.Arg70Leu Uncertain significance ★★ ⚠ same type
STAT4 p.Arg87Lys Uncertain significance ★★ ⚠ same type
STAT4 p.Asp513Val Uncertain significance ★★ ⚠ same type

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/stat4-p-thr446ile (accessed [today's date]).

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