Is STAT4 p.Ala740Val (c.2219C>T) pathogenic?

STAT4 p.Ala740Val (c.2219C>T) is classified Uncertain significance in STAT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-08). AlphaMissense: likely benign (0.1671); Absent from gnomAD v4.1.

How common is STAT4 p.Ala740Val (c.2219C>T) in the general population?

STAT4 p.Ala740Val (c.2219C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about STAT4 p.Ala740Val (c.2219C>T)?

AlphaMissense predicts likely benign (score 0.1671) — an in-silico prediction, not a clinical call.

STAT4 p.Ala740Val

c.2219C>T · rs2125134034 · VCV1377331

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1671 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1671	likely benign
REVEL	0.553	indeterminate
SaProt	LLR -5.74	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.20 · evaluated, not missing
Pangolin	Δ0.27	loss · gain 0.03 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 1,642 bp · p 1.5e-05 · regional, not allelic
Overall
CADD	24.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: STAT4
Protein: p.Ala740Val
Coding: c.2219C>T
MANE Select: NM_003151
dbSNP: rs2125134034
Type: single nucleotide variant
Location: chr2:191030973 (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.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
STAT4 p.Gly393Ala 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-ala740val (accessed [today's date]).

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