Is STAT4 p.Ile653Met (c.1959T>G) pathogenic?

STAT4 p.Ile653Met (c.1959T>G) is classified Likely benign in STAT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-06). AlphaMissense: likely benign (0.2061); Rare (popmax 0.112%, sas).

How common is STAT4 p.Ile653Met (c.1959T>G) in the general population?

STAT4 p.Ile653Met (c.1959T>G) is rare (popmax 0.112%, sas) (gnomAD).

What do computational predictors say about STAT4 p.Ile653Met (c.1959T>G)?

AlphaMissense predicts likely benign (score 0.2061) — an in-silico prediction, not a clinical call.

STAT4 p.Ile653Met

c.1959T>G · rs749296968 · VCV1410991

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2061 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.112%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2061	likely benign
REVEL	0.324	indeterminate
SaProt	LLR -8.53	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.61	GERP -3.7, phastCons 0.94
Regional constraint	o/e 0.48	unconstrained · MANE · 1,552 bp · p 1e-10 · regional, not allelic
Overall
CADD	19.19	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 0.112% South Asian · 102/91,084 alleles

Filtering AF 0.0944% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0877%

Overall 0.00663% 107/1,614,204 alleles · rare exomes 100/1,461,890 · genomes 7/152,314 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.112%	893
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)	0.000254%	393,345

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.Ile653Met
Coding: c.1959T>G
MANE Select: NM_003151
dbSNP: rs749296968
Type: single nucleotide variant
Location: chr2:191033043 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.93 (gnomAD)
Structure: AlphaFold pLDDT 86.87
Residue 653: the sh2 domain

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

Similar variants

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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-ile653met (accessed [today's date]).

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