Is STAT4 p.Glu425Asp (c.1275A>T) pathogenic?

STAT4 p.Glu425Asp (c.1275A>T) is classified Uncertain significance in STAT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-30). AlphaMissense: likely pathogenic (0.6445); Very rare (popmax 8.99e-05%, nfe).

How common is STAT4 p.Glu425Asp (c.1275A>T) in the general population?

STAT4 p.Glu425Asp (c.1275A>T) is very rare (popmax 8.99e-05%, nfe) (gnomAD).

What do computational predictors say about STAT4 p.Glu425Asp (c.1275A>T)?

AlphaMissense predicts likely pathogenic (score 0.6445) — an in-silico prediction, not a clinical call.

STAT4 p.Glu425Asp

c.1275A>T · rs1218971959 · VCV1444097

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6445 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.99e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6445	likely pathogenic
REVEL	0.809	moderately pathogenic-leaning
SaProt	LLR -8.30	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.18	GERP -0.002, phastCons 0.96
Regional constraint	o/e 0.77	unconstrained · MANE · 114 kb · p 8.5e-09 · regional, not allelic
Overall
CADD	21.4	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 8.99e-05% European (non-Finnish) · 1/1,112,518 alleles

Overall 0.000658% 1/152,090 alleles · very rare

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.Glu425Asp
Coding: c.1275A>T
MANE Select: NM_003151
dbSNP: rs1218971959
Type: single nucleotide variant
Location: chr2:191041125 (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-glu425asp (accessed [today's date]).

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