# NM_007315.4(STAT1):c.2202G>T (p.Val734=)

https://sugi.bio/variant/stat1-p-val734

## Summary

**STAT1 p.Val734= (c.2202G>T)** is classified **Likely benign** in STAT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-10). Very rare (popmax 0.004%, afr); Associated with immunodeficiency 31B.

**At a glance:** Likely benign · review: Single submitter · rsID rs1165194803 · 1 submitter · 3 linked conditions · very rare (popmax 0.004%, afr)

## For patients & families {#patients}

This is a change in the STAT1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to immunodeficiency 31B.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Diagnostic panels | STAT1 is a diagnostic-grade gene on 4 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017612/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [STAT1](https://sugi.bio/atlas/gene/STAT1/) |
| Protein change (HGVS p.) | p.Val734= |
| Coding change (HGVS c.) | c.2202G>T |
| MANE Select transcript | [NM_007315](https://www.ncbi.nlm.nih.gov/nuccore/NM_007315) |
| dbSNP | [rs1165194803](https://www.ncbi.nlm.nih.gov/snp/rs1165194803/) |
| Variant type | single nucleotide variant |
| Location | chr2:190974866-190974866 (GRCh38) |
| ClinVar | [VCV1968914](https://www.ncbi.nlm.nih.gov/clinvar/variation/1968914/) |

**All HGVS expressions:** `LRG_111:g.44385G>T`, `LRG_111t1:c.2202G>T`, `NC_000002.11:g.191839592C>A`, `NC_000002.12:g.190974866C>A`, `NG_008294.1:g.44385G>T`, `NM_001384880.1:c.2142G>T`, `NM_001384881.1:c.2208G>T`, `NM_001384882.1:c.2196G>T`, `NM_001384883.1:c.2103G>T`, `NM_001384884.1:c.1965G>T`, `NM_001384885.1:c.2043G>T`, `NM_001384886.1:c.2226G>T`, `NM_001384887.1:c.2109G>T`, `NM_001384888.1:c.2172G>T`, `NM_001384889.1:c.2190G>T`, `NM_001384890.1:c.2112G>T`, `NM_001384891.1:c.2238G>T`, `NM_007315.4:c.2202G>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.252, GERP -2.58, phastCons 0.747 — weakly conserved position
- CADD: **PHRED 7.534**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.004%** (afr) · FAF95 0.00106% · FAF99 0.000494% · 3/75,056 in the highest group · 4/1,614,216 alleles overall — very rare (popmax 0.004%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.004% | 25,019 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,508 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**STAT1** population constraint: LOEUF 0.271, pLI 1, missense-Z 7.0276; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **immunodeficiency 31B** — Definitive (AR)
- **Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency** — Definitive (AD)
- **autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **734** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 87.78, 71% of residues very-high.

**10 experimental structure(s)** (PDB): [1BF5](https://www.rcsb.org/structure/1BF5), [1YVL](https://www.rcsb.org/structure/1YVL), [2KA6](https://www.rcsb.org/structure/2KA6), [3WWT](https://www.rcsb.org/structure/3WWT), [7NUF](https://www.rcsb.org/structure/7NUF), [8D3F](https://www.rcsb.org/structure/8D3F).

## What this gene does {#gene-function}

*Describes the biological roles of STAT1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** STAT1's established molecular role includes RNA polymerase II transcription regulatory region sequence-specific DNA binding. In Reactome, STAT1 is annotated in disease pathway(s) including **SARS-CoV-2 activates/modulates innate and adaptive immune responses**, **Signaling by ALK fusions and activated point mutants**.

**Disease mechanism (Reactome):** STAT1 loss or alteration is curated in [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671), [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370), [Signaling by PDGFRA extracellular domain mutants](https://reactome.org/content/detail/R-HSA-9673770).

### Pathways affected {#pathways}

STAT1 participates in **31 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671) | curated |
| ⚕ [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370) | curated |
| ⚕ [Signaling by PDGFRA extracellular domain mutants](https://reactome.org/content/detail/R-HSA-9673770) | curated |
| ⚕ [Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants](https://reactome.org/content/detail/R-HSA-9673767) | curated |
| ⚕ [Signaling by cytosolic FGFR1 fusion mutants](https://reactome.org/content/detail/R-HSA-1839117) | curated |
| ⚕ [Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants](https://reactome.org/content/detail/R-HSA-9670439) | curated |
| [Downstream signal transduction](https://reactome.org/content/detail/R-HSA-186763) | curated |
| [ISG15 antiviral mechanism](https://reactome.org/content/detail/R-HSA-1169408) | curated |
| [Interferon alpha/beta signaling](https://reactome.org/content/detail/R-HSA-909733) | curated |
| [Interleukin-20 family signaling](https://reactome.org/content/detail/R-HSA-8854691) | curated |
| [Interleukin-21 signaling](https://reactome.org/content/detail/R-HSA-9020958) | curated |
| [Interleukin-27 signaling](https://reactome.org/content/detail/R-HSA-9020956) | curated |
| [Interleukin-35 Signalling](https://reactome.org/content/detail/R-HSA-8984722) | curated |
| [Interleukin-4 and Interleukin-13 signaling](https://reactome.org/content/detail/R-HSA-6785807) | curated |
| [Interleukin-6 signaling](https://reactome.org/content/detail/R-HSA-1059683) | curated |
| [Interleukin-9 signaling](https://reactome.org/content/detail/R-HSA-8985947) | curated |
| [PKR-mediated signaling](https://reactome.org/content/detail/R-HSA-9833482) | curated |
| [Regulation of PD-L1(CD274) transcription](https://reactome.org/content/detail/R-HSA-9909649) | curated |
| [Signaling by SCF-KIT](https://reactome.org/content/detail/R-HSA-1433557) | curated |
| [Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells](https://reactome.org/content/detail/R-HSA-9860927) | curated |
| [Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)](https://reactome.org/content/detail/R-HSA-9942503) | other |
| [Downregulation of SMAD2/3:SMAD4 transcriptional activity](https://reactome.org/content/detail/R-HSA-2173795) | other |
| [Growth hormone receptor signaling](https://reactome.org/content/detail/R-HSA-982772) | electronic |
| [Inactivation of CSF3 (G-CSF) signaling](https://reactome.org/content/detail/R-HSA-9705462) | electronic |
| [Interferon gamma signaling](https://reactome.org/content/detail/R-HSA-877300) | other |
| [NOTCH3 Intracellular Domain Regulates Transcription](https://reactome.org/content/detail/R-HSA-9013508) | electronic |
| [Regulation of IFNA/IFNB signaling](https://reactome.org/content/detail/R-HSA-912694) | other |
| [Regulation of IFNG signaling](https://reactome.org/content/detail/R-HSA-877312) | other |
| [Regulation of RUNX2 expression and activity](https://reactome.org/content/detail/R-HSA-8939902) | electronic |
| [Signaling by CSF1 (M-CSF) in myeloid cells](https://reactome.org/content/detail/R-HSA-9680350) | electronic |
| [Signaling by CSF3 (G-CSF)](https://reactome.org/content/detail/R-HSA-9674555) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** RNA polymerase II transcription regulatory region sequence-specific DNA binding, RNA polymerase II cis-regulatory region sequence-specific DNA binding, RNA polymerase II core promoter sequence-specific DNA binding, DNA-binding transcription factor activity, RNA polymerase II-specific, transcription corepressor binding, transcription coactivator binding.

**Biological process:** negative regulation of endothelial cell proliferation, positive regulation of defense response to virus by host, regulation of transcription by RNA polymerase II, cell surface receptor signaling pathway via JAK-STAT, negative regulation of angiogenesis, positive regulation of interferon-alpha production.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-10.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-03-10 |

## Associated conditions {#conditions}

[immunodeficiency 31B](https://sugi.bio/atlas/disease/immunodeficiency-31b/), [autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome](https://sugi.bio/atlas/disease/autoimmune-enteropathy-and-endocrinopathy-susceptibility-to-chronic-infections-syndrome/), [Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency](https://sugi.bio/atlas/disease/mendelian-susceptibility-to-mycobacterial-diseases-due-to-partial-stat1-deficiency/).

**Reported phenotype names (ClinVar):** Immunodeficiency 31B, Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome, Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency, IMMUNODEFICIENCY 31B, MYCOBACTERIAL AND VIRAL INFECTIONS, AUTOSOMAL RECESSIVE, STAT1 DEFICIENCY, AUTOSOMAL RECESSIVE, Immunodeficiency 31C, Immunodeficiency 31C, autosomal dominant, IMMUNODEFICIENCY 31A, MYCOBACTERIOSIS, AUTOSOMAL DOMINANT, STAT1 DEFICIENCY, AUTOSOMAL DOMINANT, Immunodeficiency 31a.

## Similar variants {#similar}

Related STAT1 variant pages (same residue, condition, or type): [STAT1 p.Val734fs](/variant/stat1-p-val734fs), [STAT1 p.Ala267Val](/variant/stat1-p-ala267val), [STAT1 p.Arg274Gln](/variant/stat1-p-arg274gln), [STAT1 p.Arg274Gly](/variant/stat1-p-arg274gly), [STAT1 p.Arg274Trp](/variant/stat1-p-arg274trp), [STAT1 p.Asp171Asn](/variant/stat1-p-asp171asn), [STAT1 p.Asp292Glu](/variant/stat1-p-asp292glu), [STAT1 p.Cys324Arg](/variant/stat1-p-cys324arg).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1968914). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*