Is STAT1 p.Ala589Ser (c.1765G>T) pathogenic?

STAT1 p.Ala589Ser (c.1765G>T) is classified Uncertain significance in STAT1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-05-16). AlphaMissense: likely benign (0.0779); Ultra-rare (popmax 0.0254%, afr); Associated with Inborn genetic diseases.

How common is STAT1 p.Ala589Ser (c.1765G>T) in the general population?

STAT1 p.Ala589Ser (c.1765G>T) is ultra-rare (popmax 0.0254%, afr) (gnomAD).

What do computational predictors say about STAT1 p.Ala589Ser (c.1765G>T)?

AlphaMissense predicts likely benign (score 0.0779) — an in-silico prediction, not a clinical call.

STAT1 p.Ala589Ser

Q: What condition is associated with STAT1 p.Ala589Ser (c.1765G>T)?

STAT1 p.Ala589Ser (c.1765G>T) is associated with Inborn genetic diseases, immunodeficiency 31B, autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome (ClinVar).

c.1765G>T · rs745491762 · VCV424473

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0779 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0254%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0779	likely benign
REVEL	0.328	indeterminate
SaProt	LLR -8.20	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 1.9, phastCons 0.99
Regional constraint	o/e 0.42	unconstrained · MANE · 15 kb · p 1.6e-32 · regional, not allelic
Overall
CADD	19.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0254% African / African-American · 19/74,920 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.00124% 20/1,614,070 alleles · ultra-rare exomes 11/1,461,870 · genomes 9/152,200 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0254%	3,943
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Ala589Ser
Coding: c.1765G>T
MANE Select: NM_007315
dbSNP: rs745491762
Type: single nucleotide variant
Location: chr2:190978964 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.78 · 10 PDB
Residue 589: an α-helix; the sh2 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: immunodeficiency 31B autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency

Similar variants

STAT1 p.Ala589Thr Uncertain significance ★★ ⚠ same residue
STAT1 p.Ala589Pro Uncertain significance ★ ⚠ 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

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-ala589ser (accessed [today's date]).

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