# NM_004972.4(JAK2):c.1284T>C (p.Ser428=)

https://sugi.bio/variant/jak2-p-ser428

## Summary

**JAK2 p.Ser428= (c.1284T>C)** is classified **Benign** in JAK2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-26). Low-frequency (popmax 2.74%, afr).

**At a glance:** Benign · review: Multiple submitters · rsID rs2230727 · 3 submitters · low-frequency (popmax 2.74%, afr)

## For patients & families {#patients}

This is a change in the JAK2 gene that is classified as benign — not considered disease-causing, submitted by 3 submitters.

*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 | [JAK2](https://sugi.bio/atlas/gene/JAK2/) |
| Protein change (HGVS p.) | p.Ser428= |
| Coding change (HGVS c.) | c.1284T>C |
| MANE Select transcript | [NM_004972](https://www.ncbi.nlm.nih.gov/nuccore/NM_004972) |
| dbSNP | [rs2230727](https://www.ncbi.nlm.nih.gov/snp/rs2230727/) |
| Variant type | single nucleotide variant |
| Location | chr9:5066747-5066747 (GRCh38) |
| ClinVar | [VCV780782](https://www.ncbi.nlm.nih.gov/clinvar/variation/780782/) |

**All HGVS expressions:** `LRG_612:g.86503T>C`, `LRG_612t1:c.1284T>C`, `NC_000009.11:g.5066747T>C`, `NC_000009.12:g.5066747T>C`, `NG_009904.1:g.86503T>C`, `NG_046969.1:g.123964A>G`, `NM_001322194.2:c.1284T>C`, `NM_001322195.2:c.1284T>C`, `NM_001322196.2:c.1284T>C`, `NM_001322198.2:c.69T>C`, `NM_001322199.2:c.69T>C`, `NM_001322204.2:c.837T>C`, `NM_004972.4:c.1284T>C`, `NR_169763.1:n.1768T>C`, `NR_169764.1:n.1685T>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 (below), not from a missing predictor score.
- Conservation: phyloP 0.88, GERP -2.31, phastCons 1 — weakly conserved position
- CADD: **PHRED 8.358**. 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 JAK2 (1,548 scored positions, the nearest 3 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 **2.74%** (afr) · FAF95 2.64% · FAF99 2.6% · 2,002/73,096 in the highest group · 2,207/1,580,522 alleles overall — low-frequency (popmax 2.74%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 2.74% | 37 |
| Remaining individuals (not grpmax-eligible) | 0.181% | 553 |
| Middle Eastern | 0.135% | 738 |
| Admixed American | 0.132% | 755 |
| European (non-Finnish) | 0.00129% | 77,738 |
| South Asian | 0.00117% | 85,474 |

*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}

**JAK2** population constraint: LOEUF 0.848, pLI 2.2544e-06, missense-Z -0.029992. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **428** lies in the sh2; atypical domain.

AlphaFold model confidence (whole protein): pLDDT 87.46, 68% of residues very-high.

**171 experimental structure(s)** (PDB): [10PJ](https://www.rcsb.org/structure/10PJ), [29RX](https://www.rcsb.org/structure/29RX), [29RY](https://www.rcsb.org/structure/29RY), [2B7A](https://www.rcsb.org/structure/2B7A), [2W1I](https://www.rcsb.org/structure/2W1I), [2XA4](https://www.rcsb.org/structure/2XA4) — incl. mutant structure 4E6D.

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

*Describes the biological roles of JAK2 (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:** JAK2's established molecular role includes protein tyrosine kinase activity. p.Ser428= falls in the sh2; atypical domain. In Reactome, JAK2 is annotated in disease pathway(s) including **Paradoxical activation of RAF signaling by kinase inactive BRAF**, **Potential therapeutics for SARS**.

**Disease mechanism (Reactome):** JAK2 loss or alteration is curated in [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955), [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191), [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952).

### Pathways affected {#pathways}

JAK2 participates in **39 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955) | curated |
| ⚕ [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191) | curated |
| ⚕ [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952) | curated |
| ⚕ [Signaling by RAF1 mutants](https://reactome.org/content/detail/R-HSA-9656223) | curated |
| ⚕ [Signaling by moderate kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802946) | curated |
| ⚕ [Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants](https://reactome.org/content/detail/R-HSA-9670439) | curated |
| ⚕ [Signaling downstream of RAS mutants](https://reactome.org/content/detail/R-HSA-9649948) | curated |
| [Cyclin D associated events in G1](https://reactome.org/content/detail/R-HSA-69231) | curated |
| [Factors involved in megakaryocyte development and platelet production](https://reactome.org/content/detail/R-HSA-983231) | curated |
| [IFNG signaling activates MAPKs](https://reactome.org/content/detail/R-HSA-9732724) | curated |
| [IL-6-type cytokine receptor ligand interactions](https://reactome.org/content/detail/R-HSA-6788467) | curated |
| [Interferon gamma signaling](https://reactome.org/content/detail/R-HSA-877300) | curated |
| [Interleukin receptor SHC signaling](https://reactome.org/content/detail/R-HSA-912526) | curated |
| [Interleukin-20 family signaling](https://reactome.org/content/detail/R-HSA-8854691) | 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 |
| [MAPK1 (ERK2) activation](https://reactome.org/content/detail/R-HSA-112411) | curated |
| [MAPK3 (ERK1) activation](https://reactome.org/content/detail/R-HSA-110056) | curated |
| [RAF activation](https://reactome.org/content/detail/R-HSA-5673000) | curated |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [RMTs methylate histone arginines](https://reactome.org/content/detail/R-HSA-3214858) | curated |
| [Signaling by SCF-KIT](https://reactome.org/content/detail/R-HSA-1433557) | curated |
| [Activation of STAT3 by cadherin engagement](https://reactome.org/content/detail/R-HSA-9958825) | electronic |
| [Erythropoietin activates Phosphoinositide-3-kinase (PI3K)](https://reactome.org/content/detail/R-HSA-9027276) | electronic |
| [Erythropoietin activates Phospholipase C gamma (PLCG)](https://reactome.org/content/detail/R-HSA-9027277) | electronic |
| [Erythropoietin activates RAS](https://reactome.org/content/detail/R-HSA-9027284) | 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-12 signaling](https://reactome.org/content/detail/R-HSA-9020591) | electronic |
| [Interleukin-23 signaling](https://reactome.org/content/detail/R-HSA-9020933) | electronic |
| [Interleukin-27 signaling](https://reactome.org/content/detail/R-HSA-9020956) | electronic |
| [Interleukin-3, Interleukin-5 and GM-CSF signaling](https://reactome.org/content/detail/R-HSA-512988) | electronic |
| [Interleukin-6 signaling](https://reactome.org/content/detail/R-HSA-1059683) | electronic |
| [Prolactin receptor signaling](https://reactome.org/content/detail/R-HSA-1170546) | electronic |
| [Regulation of IFNG signaling](https://reactome.org/content/detail/R-HSA-877312) | electronic |
| [Signaling by CSF3 (G-CSF)](https://reactome.org/content/detail/R-HSA-9674555) | electronic |
| [Signaling by Erythropoietin](https://reactome.org/content/detail/R-HSA-9006335) | electronic |
| [Signaling by Leptin](https://reactome.org/content/detail/R-HSA-2586552) | electronic |

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

**Molecular function:** protein tyrosine kinase activity, non-membrane spanning protein tyrosine kinase activity, signaling receptor binding, protein kinase binding, heme binding, histone H3Y41 kinase activity.

**Biological process:** cell adhesion, cell surface receptor signaling pathway via JAK-STAT, positive regulation of platelet activation, positive regulation of cell-substrate adhesion, cytokine-mediated signaling pathway, tumor necrosis factor-mediated signaling pathway.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-26.

**Submitter consensus:** unanimous (3/3 Benign).

**Submission history:** 2 submissions (2021–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Benign | criteria provided, single submitter | clinical testing | 2021-05-03 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-26 |

**Reported phenotype names (ClinVar):** not provided, not specified, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related JAK2 variant pages (same residue, condition, or type): [JAK2 p.Arg133Trp](/variant/jak2-p-arg133trp), [JAK2 p.His587Asn](/variant/jak2-p-his587asn), [JAK2 p.Ile899Val](/variant/jak2-p-ile899val), [JAK2 p.Met32Val](/variant/jak2-p-met32val), [JAK2 p.Asn986=](/variant/jak2-p-asn986), [JAK2 p.His163=](/variant/jak2-p-his163), [JAK2 c.1641+6T>C](/variant/jak2-c-1641-plus-6t-c), [JAK2 p.Ala835Asp](/variant/jak2-p-ala835asp).

### 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 780782). 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.*