# NM_012448.4(STAT5B):c.1101C>A (p.Pro367=)

https://sugi.bio/variant/stat5b-p-pro367

## Summary

**STAT5B p.Pro367= (c.1101C>A)** is classified **Benign/Likely benign** in STAT5B (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-05-09). Common (popmax 5.71%, mid) — too common for a highly-penetrant pathogenic allele; Associated with growth hormone insensitivity with immune dysregulation 1, autosomal recessive.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs61749920 · 8 submitters · 1 linked condition · common (popmax 5.71%, mid) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the STAT5B gene that is classified as benign/likely benign — not considered disease-causing, submitted by 8 submitters, 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.Pro367= |
| Coding change (HGVS c.) | c.1101C>A |
| MANE Select transcript | [NM_012448](https://www.ncbi.nlm.nih.gov/nuccore/NM_012448) |
| dbSNP | [rs61749920](https://www.ncbi.nlm.nih.gov/snp/rs61749920/) |
| Variant type | single nucleotide variant |
| Location | chr17:42218219-42218219 (GRCh38) |
| ClinVar | [VCV199127](https://www.ncbi.nlm.nih.gov/clinvar/variation/199127/) |

**All HGVS expressions:** `LRG_192:g.63188C>A`, `LRG_192t1:c.1101C>A`, `NC_000017.10:g.40370237G>T`, `NC_000017.11:g.42218219G>T`, `NG_007271.1:g.63188C>A`, `NM_012448.4:c.1101C>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 5.71%, mid) — too common for a highly-penetrant pathogenic allele.

- **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 -4.69, GERP -4.21 — fast-evolving / accelerated position
- CADD: **PHRED 9.509**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for STAT5B (1,281 scored positions, the nearest 2 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **5.71%** (mid) · FAF95 5.38% · FAF99 5.33% · 346/6,062 in the highest group · 39,726/1,614,132 alleles overall — common (popmax 5.71%, mid) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 5.71% | 18 |
| South Asian | 5.51% | 18 |
| Ashkenazi Jewish (not grpmax-eligible) | 5.02% | 20 |
| Remaining individuals (not grpmax-eligible) | 2.93% | 34 |
| European (non-Finnish) | 2.42% | 41 |
| Finnish (not grpmax-eligible) | 1.87% | 53 |
| Admixed American | 1.57% | 64 |
| African / African-American | 0.428% | 234 |
| Amish (not grpmax-eligible) | 0.219% | 456 |
| East Asian | 0.0156% | 6,412 |

*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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-05-09.

**Submitter consensus:** conflicting (7 Benign, 1 Likely benign).

**Submission history:** 8 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2015-06-23 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2026-05-09 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2016-03-29 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2018-07-16 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-02 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2022-04-23 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-28 |

## 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, not specified, not provided, AllHighlyPenetrant, none provided, GROWTH HORMONE INSENSITIVITY SYNDROME WITH IMMUNE DYSREGULATION 1, AUTOSOMAL RECESSIVE, Laron syndrome with immunodeficiency, GROWTH HORMONE INSENSITIVITY DUE TO POSTRECEPTOR DEFECT, LARON SYNDROME DUE TO POSTRECEPTOR DEFECT.

## Similar variants {#similar}

Related STAT5B variant pages (same residue, condition, or type): [STAT5B p.Pro367Arg](/variant/stat5b-p-pro367arg), [STAT5B p.Pro367His](/variant/stat5b-p-pro367his), [STAT5B p.Pro367Leu](/variant/stat5b-p-pro367leu), [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).

### 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 199127). 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.*