Is STAT4 p.His221Arg (c.662A>G) pathogenic?

STAT4 p.His221Arg (c.662A>G) is classified Conflicting classifications of pathogenicity in STAT4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-18). AlphaMissense: likely benign (0.072); Ultra-rare (popmax 0.0363%, eas).

How common is STAT4 p.His221Arg (c.662A>G) in the general population?

STAT4 p.His221Arg (c.662A>G) is ultra-rare (popmax 0.0363%, eas) (gnomAD).

What do computational predictors say about STAT4 p.His221Arg (c.662A>G)?

AlphaMissense predicts likely benign (score 0.072) — an in-silico prediction, not a clinical call.

STAT4 p.His221Arg

c.662A>G · rs780454944 · VCV3171118

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.072 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0363%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.072	likely benign
REVEL	0.122	moderately benign-leaning
SaProt	LLR -6.94	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.67	GERP 0.72, phastCons 0.031
Regional constraint	o/e 0.77	unconstrained · MANE · 114 kb · p 8.5e-09 · regional, not allelic
Overall
CADD	12.84	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 0.0363% East Asian · 16/44,100 alleles

Filtering AF 0.0227% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0185%

Overall 0.000995% 16/1,607,562 alleles · ultra-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.His221Arg
Coding: c.662A>G
MANE Select: NM_003151
dbSNP: rs780454944
Type: single nucleotide variant
Location: chr2:191064927 (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-his221arg (accessed [today's date]).

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