Is STAT1 p.Phe364Leu (c.1090T>C) pathogenic?

STAT1 p.Phe364Leu (c.1090T>C) is classified Conflicting classifications of pathogenicity in STAT1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-15). AlphaMissense: likely pathogenic (0.9198); Ultra-rare (popmax 0.0164%, nfe); Associated with autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome.

What condition is associated with STAT1 p.Phe364Leu (c.1090T>C)?

STAT1 p.Phe364Leu (c.1090T>C) is associated with autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome, immunodeficiency 31B, Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency (ClinVar).

How common is STAT1 p.Phe364Leu (c.1090T>C) in the general population?

STAT1 p.Phe364Leu (c.1090T>C) is ultra-rare (popmax 0.0164%, nfe) (gnomAD).

What do computational predictors say about STAT1 p.Phe364Leu (c.1090T>C)?

AlphaMissense predicts likely pathogenic (score 0.9198) — an in-silico prediction, not a clinical call.

STAT1 p.Phe364Leu

Q: How is STAT1-related autoimmune enteropathy and endocrinopathy-susceptibility to chronic infections syndrome inherited?

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

c.1090T>C · rs759722579 · VCV333283

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9198 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome

Computational evidence

Protein change
AlphaMissense	0.9198	likely pathogenic
REVEL	0.302	indeterminate
SaProt	LLR -9.47	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.49, phastCons 1
Regional constraint	o/e 0.19	constrained · MANE · 9,439 bp · p 1.9e-19 · regional, not allelic
Overall
CADD	24.1	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 0.0164% European (non-Finnish) · 186/1,137,198 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.0127% 198/1,559,400 alleles · ultra-rare exomes 188/1,407,140 · genomes 10/152,260 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0164%	6,114
Remaining individualsnot grpmax-eligible	0.0116%	8,629
African / African-American	0.00409%	24,458
Finnishnot grpmax-eligible	0.00159%	62,922
South Asian	0.00115%	87,214

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.Phe364Leu
Coding: c.1090T>C
MANE Select: NM_007315
dbSNP: rs759722579
Type: single nucleotide variant
Location: chr2:190989622 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.78 · 10 PDB
Residue 364: a β-strand

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

Disease context

autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: immunodeficiency 31B Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency

For STAT1-related autoimmune enteropathy and endocrinopathy-susceptibility to chronic infections syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy

Similar variants

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
STAT1 p.Gln271Pro Pathogenic/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-phe364leu (accessed [today's date]).

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