Is STAT1 p.Ser25fs (c.71_74dup) pathogenic?

STAT1 p.Ser25fs (c.7174dup) is classified Pathogenic in STAT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-02). Very rare (popmax 8.48e-05%, nfe); Associated with Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency.

What condition is associated with STAT1 p.Ser25fs (c.71_74dup)?

STAT1 p.Ser25fs (c.71_74dup) is associated with Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency, immunodeficiency 31B, autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome (ClinVar).

How common is STAT1 p.Ser25fs (c.71_74dup) in the general population?

STAT1 p.Ser25fs (c.71_74dup) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

STAT1 p.Ser25fs

Q: How is Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency inherited?

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

c.71_74dup · rs1382612689 · VCV1457465

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency

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 3 of 25
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.6	GERP -0.54, phastCons 1
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,938 alleles

Overall 6.2e-05% 1/1,613,906 alleles · very rare exomes 0/1,461,766 · genomes 1/152,140 · 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.Ser25fs
Coding: c.71_74dup
MANE Select: NM_007315
dbSNP: rs1382612689
Type: Duplication
Location: chr2:191009929 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.78 · 10 PDB
Residue 25: a β-strand

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

Disease context

Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: immunodeficiency 31B autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome

For Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

STAT1 p.Ser25= Likely benign ★★ same residue
STAT1 c.1098-5dup Benign/Likely benign ★★ same condition
STAT1 c.1633-13dup Likely benign ★★ 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-ser25fs (accessed [today's date]).

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