Is STAT1 p.Asp447Glu (c.1341C>A) pathogenic?

STAT1 p.Asp447Glu (c.1341C>A) is classified Conflicting classifications of pathogenicity in STAT1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-11-23). AlphaMissense: likely benign (0.1762); Rare (popmax 0.132%, mid); Associated with immunodeficiency 31B.

How common is STAT1 p.Asp447Glu (c.1341C>A) in the general population?

STAT1 p.Asp447Glu (c.1341C>A) is rare (popmax 0.132%, mid) (gnomAD).

What do computational predictors say about STAT1 p.Asp447Glu (c.1341C>A)?

AlphaMissense predicts likely benign (score 0.1762) — an in-silico prediction, not a clinical call.

STAT1 p.Asp447Glu

Q: What condition is associated with STAT1 p.Asp447Glu (c.1341C>A)?

STAT1 p.Asp447Glu (c.1341C>A) is associated with immunodeficiency 31B, autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome, Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency (ClinVar).

Q: How is Susceptibility to viral and mycobacterial infections due to STAT1 deficiency inherited?

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

c.1341C>A · rs140351189 · VCV333273

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1762 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.132%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency 31B

Computational evidence

Protein change
AlphaMissense	0.1762	likely benign
REVEL	0.289	benign-leaning
SaProt	LLR -6.62	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.85	GERP -2.5, phastCons 1
Regional constraint	o/e 0.42	unconstrained · MANE · 15 kb · p 1.6e-32 · regional, not allelic
Overall
CADD	16.62	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 0.132% Middle Eastern · 8/6,060 alleles

Filtering AF 0.0657% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0479%

Overall 0.0128% 206/1,613,570 alleles · rare exomes 189/1,461,354 · genomes 17/152,216 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.132%	758
South Asian	0.0428%	2,335
Remaining individualsnot grpmax-eligible	0.024%	4,167
European (non-Finnish)	0.012%	8,366
Admixed American	0.00333%	30,012
African / African-American	0.00133%	74,982

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.Asp447Glu
Coding: c.1341C>A
MANE Select: NM_007315
dbSNP: rs140351189
Type: single nucleotide variant
Location: chr2:190984316 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.78 · 10 PDB
Residue 447: a β-strand

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

Disease context

immunodeficiency 31B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Susceptibility to viral and mycobacterial infections due to STAT1 deficiency (Orphanet):

Inheritance: Autosomal recessive

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-asp447glu (accessed [today's date]).

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