# NM_012448.4(STAT5B):c.2176A>G (p.Met726Val)

https://sugi.bio/variant/stat5b-p-met726val

## Summary

**STAT5B p.Met726Val (c.2176A>G)** is classified **Uncertain significance** in STAT5B (ClinVar, Single submitter, 1 submitter; last evaluated 2018-12-27). AlphaMissense: likely benign (0.1045); Very rare (popmax 8.47e-05%, nfe); Associated with growth hormone insensitivity with immune dysregulation 1, autosomal recessive.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1598292098 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the STAT5B gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to growth hormone insensitivity with immune dysregulation 1, autosomal recessive.

*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 dominant, Autosomal recessive |
| Age of onset (of this condition) | Childhood, Infancy, Neonatal |
| Diagnostic panels | STAT5B is a diagnostic-grade gene on 7 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018311/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [STAT5B](https://sugi.bio/atlas/gene/STAT5B/) |
| Protein change (HGVS p.) | p.Met726Val |
| Coding change (HGVS c.) | c.2176A>G |
| MANE Select transcript | [NM_012448](https://www.ncbi.nlm.nih.gov/nuccore/NM_012448) |
| dbSNP | [rs1598292098](https://www.ncbi.nlm.nih.gov/snp/rs1598292098/) |
| Variant type | single nucleotide variant |
| Location | chr17:42202401-42202401 (GRCh38) |
| ClinVar | [VCV649575](https://www.ncbi.nlm.nih.gov/clinvar/variation/649575/) |

**All HGVS expressions:** `LRG_192:g.79006A>G`, `LRG_192t1:c.2176A>G`, `NC_000017.10:g.40354419T>C`, `NC_000017.11:g.42202401T>C`, `NG_007271.1:g.79006A>G`, `NM_012448.4:c.2176A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1045)
- REVEL 0.489 (indeterminate)
- SaProt LLR -6.55 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- SpliceAI predicts **donor gain** (Δ 0.72) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.929, GERP 0.644, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.7**. 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 0.69** across the covering region of the MANE Select transcript (42,201,741–42,202,437), spanning 696 bp. Chi-square p 0.0011. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.72**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.72**.
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,180,032 in the highest group · 1/1,614,232 alleles overall — very rare (popmax 8.47e-05%, nfe).

*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}

**STAT5B** population constraint: LOEUF 0.277, pLI 1, missense-Z 5.1347. *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):

- **growth hormone insensitivity with immune dysregulation 1, autosomal recessive** — Definitive (AR)
- **growth hormone insensitivity syndrome with immune dysregulation 2, autosomal dominant** — Moderate (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 85.90, 67% of residues very-high.

**2 experimental structure(s)** (PDB): [6MBW](https://www.rcsb.org/structure/6MBW), [6MBZ](https://www.rcsb.org/structure/6MBZ).

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

*Describes the biological roles of STAT5B (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:** STAT5B's established molecular role includes DNA-binding transcription activator activity, RNA polymerase II-specific. In Reactome, STAT5B is annotated in disease pathway(s) including **STAT5 activation downstream of FLT3 ITD mutants**, **Signaling by FLT3 fusion proteins**.

**Disease mechanism (Reactome):** STAT5B loss or alteration is curated in [STAT5 activation downstream of FLT3 ITD mutants](https://reactome.org/content/detail/R-HSA-9702518), [Signaling by FLT3 fusion proteins](https://reactome.org/content/detail/R-HSA-9703465), [Signaling by cytosolic FGFR1 fusion mutants](https://reactome.org/content/detail/R-HSA-1839117).

### Pathways affected {#pathways}

STAT5B participates in **21 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [STAT5 activation downstream of FLT3 ITD mutants](https://reactome.org/content/detail/R-HSA-9702518) | curated |
| ⚕ [Signaling by FLT3 fusion proteins](https://reactome.org/content/detail/R-HSA-9703465) | 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 |
| [Interleukin-15 signaling](https://reactome.org/content/detail/R-HSA-8983432) | 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-9 signaling](https://reactome.org/content/detail/R-HSA-8985947) | curated |
| [Signaling by SCF-KIT](https://reactome.org/content/detail/R-HSA-1433557) | curated |
| [Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)](https://reactome.org/content/detail/R-HSA-9976102) | electronic |
| [Erythropoietin activates STAT5](https://reactome.org/content/detail/R-HSA-9027283) | electronic |
| [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 |
| [Interleukin-2 signaling](https://reactome.org/content/detail/R-HSA-9020558) | electronic |
| [Interleukin-3, Interleukin-5 and GM-CSF signaling](https://reactome.org/content/detail/R-HSA-512988) | electronic |
| [Interleukin-7 signaling](https://reactome.org/content/detail/R-HSA-1266695) | electronic |
| [Prolactin receptor signaling](https://reactome.org/content/detail/R-HSA-1170546) | electronic |
| [STAT5 Activation](https://reactome.org/content/detail/R-HSA-9645135) | electronic |
| [Signaling by CSF3 (G-CSF)](https://reactome.org/content/detail/R-HSA-9674555) | electronic |
| [Signaling by Leptin](https://reactome.org/content/detail/R-HSA-2586552) | electronic |

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

**Molecular function:** DNA-binding transcription activator activity, RNA polymerase II-specific, nuclear glucocorticoid receptor binding, identical protein binding, protein homodimerization activity.

**Biological process:** response to estradiol, cellular response to hormone stimulus, erythropoietin-mediated signaling pathway, positive regulation of erythrocyte differentiation, growth hormone receptor signaling pathway via JAK-STAT.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-12-27.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-12-27 |

## Associated conditions {#conditions}

[growth hormone insensitivity with immune dysregulation 1, autosomal recessive](https://sugi.bio/atlas/disease/growth-hormone-insensitivity-with-immune-dysregulation-1-autosomal-recessive/).

**Reported phenotype names (ClinVar):** Growth hormone insensitivity with immune dysregulation 1, autosomal recessive, LARON SYNDROME DUE TO POSTRECEPTOR DEFECT, GROWTH HORMONE INSENSITIVITY SYNDROME WITH IMMUNE DYSREGULATION 1, AUTOSOMAL RECESSIVE, GROWTH HORMONE INSENSITIVITY DUE TO POSTRECEPTOR DEFECT, Laron syndrome with immunodeficiency.

## Similar variants {#similar}

Related STAT5B variant pages (same residue, condition, or type): [STAT5B p.Met726Ile](/variant/stat5b-p-met726ile), [STAT5B c.1906+1G>A](/variant/stat5b-c-1906-plus-1g-a), [STAT5B p.Ala20Glu](/variant/stat5b-p-ala20glu), [STAT5B p.Ala20Val](/variant/stat5b-p-ala20val), [STAT5B p.Ala213Gly](/variant/stat5b-p-ala213gly), [STAT5B p.Ala213Ser](/variant/stat5b-p-ala213ser), [STAT5B p.Ala723Thr](/variant/stat5b-p-ala723thr), [STAT5B p.Ala785Thr](/variant/stat5b-p-ala785thr).

### 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 649575). 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.*