# NM_003153.5(STAT6):c.543G>T (p.Met181Ile)

https://sugi.bio/variant/stat6-p-met181ile

## Summary

**STAT6 p.Met181Ile (c.543G>T)** is classified **Uncertain significance** in STAT6 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-19). AlphaMissense: likely benign (0.1374); Very rare (popmax 0.00549%, sas); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00549%, sas)

## For patients & families {#patients}

This is a change in the STAT6 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [STAT6](https://sugi.bio/atlas/gene/STAT6/) |
| Protein change (HGVS p.) | p.Met181Ile |
| Coding change (HGVS c.) | c.543G>T |
| MANE Select transcript | [NM_003153](https://www.ncbi.nlm.nih.gov/nuccore/NM_003153) |
| Variant type | single nucleotide variant |
| Location | chr12:57106328-57106328 (GRCh38) |
| ClinVar | [VCV4865188](https://www.ncbi.nlm.nih.gov/clinvar/variation/4865188/) |

**All HGVS expressions:** `LRG_1369:g.30812G>T`, `LRG_1369t1:c.543G>T`, `NC_000012.11:g.57500111C>A`, `NC_000012.12:g.57106328C>A`, `NG_021272.2:g.30812G>T`, `NM_001178078.2:c.543G>T`, `NM_001178079.2:c.543G>T`, `NM_001178080.2:c.213G>T`, `NM_001178081.2:c.213G>T`, `NM_003153.5:c.543G>T`, `NR_033659.2:n.659G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1374)
- REVEL 0.047 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.353 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor gain** (Δ 0.47) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -12.393, GERP -4.41 — fast-evolving / accelerated position
- CADD: **PHRED 0.094**. 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.*
- Regional missense constraint: **o/e 0.78** across the covering region of the MANE Select transcript (57,104,761–57,108,278), spanning 3,517 bp. Chi-square p 6e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.47**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.47**, donor gain **0.00**.
- Pangolin: Δ**0.23** (gain), gain 0.23 / loss 0.02. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00549%** (sas) · FAF95 0.0021% · FAF99 0.00136% · 5/91,092 in the highest group · 5/1,614,252 alleles overall — very rare (popmax 0.00549%, sas).

*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}

**STAT6** population constraint: LOEUF 0.515, pLI 0.56138, missense-Z 3.3501. *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):

- **hyper-IgE syndrome 6, autosomal dominant, with recurrent infections** — Strong (AD)

## Protein context {#protein}

Residue **181** lies in a UniProt-annotated variant site (in).

AlphaFold model confidence (whole protein): pLDDT 77.44, 55% of residues very-high.

**7 experimental structure(s)** (PDB): [1OJ5](https://www.rcsb.org/structure/1OJ5), [4Y5U](https://www.rcsb.org/structure/4Y5U), [4Y5W](https://www.rcsb.org/structure/4Y5W), [5D39](https://www.rcsb.org/structure/5D39), [5NWM](https://www.rcsb.org/structure/5NWM), [5NWX](https://www.rcsb.org/structure/5NWX).

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

*Describes the biological roles of STAT6 (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:** STAT6's established molecular role includes RNA polymerase II transcription regulatory region sequence-specific DNA binding.


### Pathways affected {#pathways}

STAT6 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Downstream signal transduction](https://reactome.org/content/detail/R-HSA-186763) | curated |
| [Interleukin-4 and Interleukin-13 signaling](https://reactome.org/content/detail/R-HSA-6785807) | curated |
| [STAT6-mediated induction of chemokines](https://reactome.org/content/detail/R-HSA-3249367) | curated |
| [Affinity selection of immunoglobulins](https://reactome.org/content/detail/R-HSA-9938027) | electronic |
| [Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)](https://reactome.org/content/detail/R-HSA-9976102) | electronic |
| [Somatic hypermutation of immunoglobulin genes](https://reactome.org/content/detail/R-HSA-9938024) | electronic |

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

**Molecular function:** RNA polymerase II transcription regulatory region sequence-specific DNA binding, DNA-binding transcription factor activity, RNA polymerase II-specific, transcription coactivator binding, DNA-binding transcription activator activity, RNA polymerase II-specific, DNA-binding transcription factor activity, protein phosphatase binding.

**Biological process:** cell surface receptor signaling pathway via JAK-STAT, cytokine-mediated signaling pathway, interleukin-4-mediated signaling pathway, positive regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-03-19.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-03-19 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related STAT6 variant pages (same residue, condition, or type): [STAT6 p.Met181Val](/variant/stat6-p-met181val), [STAT6 p.Ala109Val](/variant/stat6-p-ala109val), [STAT6 p.Ala245Val](/variant/stat6-p-ala245val), [STAT6 p.Ala304Asp](/variant/stat6-p-ala304asp), [STAT6 p.Ala358Val](/variant/stat6-p-ala358val), [STAT6 p.Ala385Thr](/variant/stat6-p-ala385thr), [STAT6 p.Ala753Thr](/variant/stat6-p-ala753thr), [STAT6 p.Ala779Val](/variant/stat6-p-ala779val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 4865188). 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.*