Is STAT4 p.Arg643Gln (c.1928G>A) pathogenic?

STAT4 p.Arg643Gln (c.1928G>A) is classified Uncertain significance in STAT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-31). AlphaMissense: ambiguous (0.4031); Very rare (popmax 0.0011%, sas).

How common is STAT4 p.Arg643Gln (c.1928G>A) in the general population?

STAT4 p.Arg643Gln (c.1928G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about STAT4 p.Arg643Gln (c.1928G>A)?

AlphaMissense predicts ambiguous (score 0.4031) — an in-silico prediction, not a clinical call.

STAT4 p.Arg643Gln

c.1928G>A · VCV4803616

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4031 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4031	ambiguous
REVEL	0.9	moderately pathogenic-leaning
SaProt	LLR -10.58	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 1,552 bp · p 1e-10 · regional, not allelic
Overall
CADD	31.0	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 0.0011% South Asian · 1/91,082 alleles

Overall 0.000124% 2/1,614,130 alleles · very rare exomes 2/1,461,880 · genomes 0/152,250 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,082
European (non-Finnish)	8.47e-05%	1,180,026

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.Arg643Gln
Coding: c.1928G>A
MANE Select: NM_003151
Type: single nucleotide variant
Location: chr2:191033074 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.93 (gnomAD)
Structure: AlphaFold pLDDT 86.87
Residue 643: the sh2 domain

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

Similar variants

STAT4 p.Arg643= 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-arg643gln (accessed [today's date]).

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