Is STAT4 p.Arg240Trp (c.718C>T) pathogenic?

STAT4 p.Arg240Trp (c.718C>T) is classified Uncertain significance in STAT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-11). AlphaMissense: likely benign (0.203); Very rare (popmax 0.00447%, eas).

How common is STAT4 p.Arg240Trp (c.718C>T) in the general population?

STAT4 p.Arg240Trp (c.718C>T) is very rare (popmax 0.00447%, eas) (gnomAD).

What do computational predictors say about STAT4 p.Arg240Trp (c.718C>T)?

AlphaMissense predicts likely benign (score 0.203) — an in-silico prediction, not a clinical call.

STAT4 p.Arg240Trp

c.718C>T · VCV4765456

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.203 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00447%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.203	likely benign
REVEL	0.549	indeterminate
SaProt	LLR -11.96	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.52	GERP -3.9, phastCons 0.99
Regional constraint	o/e 0.77	unconstrained · MANE · 114 kb · p 8.5e-09 · regional, not allelic
Overall
CADD	23.7	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 0.00447% East Asian · 2/44,768 alleles

Filtering AF 0.000741% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000558% 9/1,613,052 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00447%	22,384
Remaining individualsnot grpmax-eligible	0.0016%	62,448
African / African-American	0.00134%	74,812
European (non-Finnish)	0.000424%	235,920

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.Arg240Trp
Coding: c.718C>T
MANE Select: NM_003151
Type: single nucleotide variant
Location: chr2:191064871 (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

Similar variants

STAT4 p.Arg240Gln Likely benign ★★ same residue
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
STAT4 p.Cys323Arg Uncertain significance ★★ ⚠ same type
STAT4 p.Gln243Lys 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-arg240trp (accessed [today's date]).

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