# NM_012448.4(STAT5B):c.1935T>C (p.Pro645=)

https://sugi.bio/variant/stat5b-p-pro645

## Summary

**STAT5B p.Pro645= (c.1935T>C)** is classified **Likely benign** in STAT5B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-04). Very rare (popmax 0.00267%, afr); Associated with growth hormone insensitivity with immune dysregulation 1, autosomal recessive.

**At a glance:** Likely benign · review: Single submitter · rsID rs767238307 · 1 submitter · 1 linked condition · very rare (popmax 0.00267%, afr)

## For patients & families {#patients}

This is a change in the STAT5B gene that is classified as likely benign — not considered disease-causing, 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.Pro645= |
| Coding change (HGVS c.) | c.1935T>C |
| MANE Select transcript | [NM_012448](https://www.ncbi.nlm.nih.gov/nuccore/NM_012448) |
| dbSNP | [rs767238307](https://www.ncbi.nlm.nih.gov/snp/rs767238307/) |
| Variant type | single nucleotide variant |
| Location | chr17:42207700-42207700 (GRCh38) |
| ClinVar | [VCV736946](https://www.ncbi.nlm.nih.gov/clinvar/variation/736946/) |

**All HGVS expressions:** `LRG_192:g.73707T>C`, `LRG_192t1:c.1935T>C`, `NC_000017.10:g.40359718A>G`, `NC_000017.11:g.42207700A>G`, `NG_007271.1:g.73707T>C`, `NM_012448.4:c.1935T>C`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.27) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.943, GERP -4.24, phastCons 0.988 — weakly conserved position
- CADD: **PHRED 11.96**. 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 deltas (raw): acceptor loss **0.27**, donor loss **0.00**, acceptor gain **0.04**, donor gain **0.00**. Largest is acceptor loss, 12 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.04**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.00267%** (afr) · FAF95 0.000442% · FAF99 0.000166% · 2/75,040 in the highest group · 5/1,614,168 alleles overall — very rare (popmax 0.00267%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,833 |
| African / African-American (grpmax) | 0.00267% | 37,520 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

Residue **645** lies in the sh2 domain; an α-helix.

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. p.Pro645= falls in the sh2 domain. 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-04.

**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 | 2025-03-04 |

## 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 with immunodeficiency, LARON SYNDROME DUE TO POSTRECEPTOR DEFECT, GROWTH HORMONE INSENSITIVITY DUE TO POSTRECEPTOR DEFECT, GROWTH HORMONE INSENSITIVITY SYNDROME WITH IMMUNE DYSREGULATION 1, AUTOSOMAL RECESSIVE.

## Similar variants {#similar}

Related STAT5B variant pages (same residue, condition, or type): [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), [STAT5B p.Arg121Leu](/variant/stat5b-p-arg121leu).

### 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 736946). 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.*