Is STAT1 p.Arg619Gln (c.1856G>A) pathogenic?

STAT1 p.Arg619Gln (c.1856G>A) is classified Uncertain significance in STAT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-05). AlphaMissense: likely benign (0.0831); Ultra-rare (popmax 0.0329%, mid); Associated with immunodeficiency 31B.

How common is STAT1 p.Arg619Gln (c.1856G>A) in the general population?

STAT1 p.Arg619Gln (c.1856G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about STAT1 p.Arg619Gln (c.1856G>A)?

AlphaMissense predicts likely benign (score 0.0831) — an in-silico prediction, not a clinical call.

STAT1 p.Arg619Gln

Q: What condition is associated with STAT1 p.Arg619Gln (c.1856G>A)?

STAT1 p.Arg619Gln (c.1856G>A) is associated with immunodeficiency 31B, autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome, Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency (ClinVar).

Q: How is Susceptibility to viral and mycobacterial infections due to STAT1 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1856G>A · rs369060692 · VCV946599

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0831 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency 31B

Computational evidence

Protein change
AlphaMissense	0.0831	likely benign
REVEL	0.26	benign-leaning
SaProt	LLR -5.04	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 1.8	GERP -1.2, phastCons 0.39
Regional constraint	o/e 0.42	unconstrained · MANE · 15 kb · p 1.6e-32 · regional, not allelic
Overall
CADD	21.2	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

Grpmax group 0.0329% Middle Eastern · 2/6,078 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00291% 47/1,613,910 alleles · ultra-rare exomes 42/1,461,768 · genomes 5/152,142 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,039
African / African-American	0.00668%	14,980
Remaining individualsnot grpmax-eligible	0.0064%	15,618
European (non-Finnish)	0.00297%	33,714
Admixed American	0.00167%	59,998

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: STAT1
Protein: p.Arg619Gln
Coding: c.1856G>A
MANE Select: NM_007315
dbSNP: rs369060692
Type: single nucleotide variant
Location: chr2:190978873 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.78 · 10 PDB
Residue 619: the sh2 domain

Full STAT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

immunodeficiency 31B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency

For Susceptibility to viral and mycobacterial infections due to STAT1 deficiency (Orphanet):

Inheritance: Autosomal recessive

Similar variants

STAT1 p.Arg619= Likely benign ★ same residue
STAT1 p.Ala267Val Pathogenic ★★ ⚠ same condition
STAT1 p.Arg274Gln Pathogenic ★★ ⚠ same condition
STAT1 p.Arg274Gly Pathogenic/Likely pathogenic ★★ same condition
STAT1 p.Arg274Trp Pathogenic ★★ same condition
STAT1 p.Asp171Asn Likely pathogenic ★★ ⚠ same condition
STAT1 p.Asp292Glu Likely pathogenic ★★ ⚠ same condition
STAT1 p.Cys324Arg Likely pathogenic ★★ same condition

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/stat1-p-arg619gln (accessed [today's date]).

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