Is STAT1 p.Thr643fs (c.1927dup) pathogenic?

STAT1 p.Thr643fs (c.1927dup) is classified Pathogenic in STAT1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2006-04-15). Very rare (popmax 8.47e-05%, nfe); Associated with immunodeficiency 31B.

What condition is associated with STAT1 p.Thr643fs (c.1927dup)?

STAT1 p.Thr643fs (c.1927dup) is associated with immunodeficiency 31B (ClinVar).

How common is STAT1 p.Thr643fs (c.1927dup) in the general population?

STAT1 p.Thr643fs (c.1927dup) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

STAT1 p.Thr643fs

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.1927dup · rs587776714 · VCV9048

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

immunodeficiency 31B

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 22 of 25
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 10	GERP 0.95, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,036 alleles

Overall 6.19e-05% 1/1,614,236 alleles · very rare exomes 1/1,461,890 · genomes 0/152,346 · joint denominator

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.Thr643fs
Coding: c.1927dup
MANE Select: NM_007315
dbSNP: rs587776714
Type: Duplication
Location: chr2:190976971 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.78 · 10 PDB
Residue 643: 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

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

Inheritance: Autosomal recessive

Similar variants

STAT1 c.1098-5dup Benign/Likely benign ★★ same condition
STAT1 c.1633-13dup Likely benign ★★ same condition
STAT1 p.Ser25fs Pathogenic ★ same condition
STAT1 p.Thr227fs Pathogenic ★ same condition
STAT1 p.Leu667_Tyr668insLysTyrLeu Uncertain significance ★ same condition
STAT1 c.1038-9dup Benign ★ same condition
STAT1 c.1098-19dup Likely benign ★ same condition
STAT1 c.2239-13dup Benign ★ 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-thr643fs (accessed [today's date]).

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