Is STAT1 p.Leu706= (c.2118G>A) pathogenic?

STAT1 p.Leu706= (c.2118G>A) is classified Uncertain significance in STAT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-08). Very rare (popmax 0.0011%, sas); Associated with Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency.

What condition is associated with STAT1 p.Leu706= (c.2118G>A)?

STAT1 p.Leu706= (c.2118G>A) 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.Leu706= (c.2118G>A) in the general population?

STAT1 p.Leu706= (c.2118G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

STAT1 p.Leu706=

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.2118G>A · VCV3750090

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

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/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.27	donor loss, 17 bp away · masked 0 · deltas
Pangolin	Δ0.21	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.9	GERP 1.9, phastCons 1
Overall
CADD	12.81	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,082 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000805% 13/1,614,148 alleles · very rare exomes 13/1,461,856 · genomes 0/152,292 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,256
South Asiangrpmax	0.0011%	91,082
European (non-Finnish)	0.000847%	118,002

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu706=
Coding: c.2118G>A
MANE Select: NM_007315
Type: single nucleotide variant
Location: chr2:190975829 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.78 · 10 PDB
Residue 706: a UniProt-annotated variant site (in imd31a; loss of gaf and isgf3 activation; impairs the nuclear accumulation of gaf but not of isgf3 in heterozygous cells stimulated by ifns; affects phosphorylation of the protein)

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.Leu706Ser Pathogenic ⚠ 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-leu706 (accessed [today's date]).

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