Is STAT1 p.Ala676Ser (c.2026G>T) pathogenic?

STAT1 p.Ala676Ser (c.2026G>T) is classified Uncertain significance in STAT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-04). AlphaMissense: likely benign (0.2382); Very rare (popmax 6.2e-05%); Associated with autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome.

What condition is associated with STAT1 p.Ala676Ser (c.2026G>T)?

STAT1 p.Ala676Ser (c.2026G>T) 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.Ala676Ser (c.2026G>T) in the general population?

STAT1 p.Ala676Ser (c.2026G>T) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about STAT1 p.Ala676Ser (c.2026G>T)?

AlphaMissense predicts likely benign (score 0.2382) — an in-silico prediction, not a clinical call.

STAT1 p.Ala676Ser

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.2026G>T · VCV4783908

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2382 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome

Computational evidence

Protein change
AlphaMissense	0.2382	likely benign
REVEL	0.749	pathogenic-leaning
SaProt	LLR -11.58	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.42	unconstrained · MANE · 15 kb · p 1.6e-32 · regional, not allelic
Overall
CADD	24.7	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 6.2e-05%

Overall 6.2e-05% 1/1,614,084 alleles · very rare exomes 0/1,461,878 · genomes 1/152,206 · 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.Ala676Ser
Coding: c.2026G>T
MANE Select: NM_007315
Type: single nucleotide variant
Location: chr2:190976873 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.78 · 10 PDB
Residue 676: an α-helix

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-ala676ser (accessed [today's date]).

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