# NM_002227.4(JAK1):c.64T>C (p.Ser22Pro)

https://sugi.bio/variant/jak1-p-ser22pro

## Summary

**JAK1 p.Ser22Pro (c.64T>C)** is classified **Uncertain significance** in JAK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-12-31). AlphaMissense: likely benign (0.1567); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2101267269 · 1 submitter · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the JAK1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [JAK1](https://sugi.bio/atlas/gene/JAK1/) |
| Protein change (HGVS p.) | p.Ser22Pro |
| Coding change (HGVS c.) | c.64T>C |
| MANE Select transcript | [NM_002227](https://www.ncbi.nlm.nih.gov/nuccore/NM_002227) |
| dbSNP | [rs2101267269](https://www.ncbi.nlm.nih.gov/snp/rs2101267269/) |
| Variant type | single nucleotide variant |
| Location | chr1:64883418-64883418 (GRCh38) |
| ClinVar | [VCV1389135](https://www.ncbi.nlm.nih.gov/clinvar/variation/1389135/) |

**All HGVS expressions:** `LRG_1398:g.189329T>C`, `LRG_1398t1:c.64T>C`, `NC_000001.10:g.65349101A>G`, `NC_000001.11:g.64883418A>G`, `NG_023402.2:g.189329T>C`, `NM_001320923.2:c.64T>C`, `NM_001321852.2:c.64T>C`, `NM_001321853.2:c.64T>C`, `NM_001321854.2:c.64T>C`, `NM_001321855.2:c.64T>C`, `NM_001321856.2:c.64T>C`, `NM_001321857.2:c.64T>C`, `NM_002227.4:c.64T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1567)
- REVEL 0.364 (indeterminate)
- SaProt LLR -7.177 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 7.953, GERP 5.35, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.7**. 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 0.71** across the covering region of the MANE Select transcript (64,860,233–64,886,264), spanning 26,031 bp. Chi-square p 2.2e-10. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**JAK1** population constraint: LOEUF 0.168, pLI 1, missense-Z 5.8688. *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):

- **autoinflammation, immune dysregulation, and eosinophilia** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 85.68, 61% of residues very-high.

**52 experimental structure(s)** (PDB): [10PI](https://www.rcsb.org/structure/10PI), [3EYG](https://www.rcsb.org/structure/3EYG), [3EYH](https://www.rcsb.org/structure/3EYH), [4E4L](https://www.rcsb.org/structure/4E4L), [4E4N](https://www.rcsb.org/structure/4E4N), [4E5W](https://www.rcsb.org/structure/4E5W).

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

*Describes the biological roles of JAK1 (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:** JAK1's established molecular role includes protein tyrosine kinase activity. In Reactome, JAK1 is annotated in disease pathway(s) including **Evasion by RSV of host interferon responses**, **Potential therapeutics for SARS**.

**Disease mechanism (Reactome):** JAK1 loss or alteration is curated in [Evasion by RSV of host interferon responses](https://reactome.org/content/detail/R-HSA-9833109), [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191), [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671).

### Pathways affected {#pathways}

JAK1 participates in **31 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Evasion by RSV of host interferon responses](https://reactome.org/content/detail/R-HSA-9833109) | curated |
| ⚕ [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191) | curated |
| ⚕ [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671) | 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 |
| [ISG15 antiviral mechanism](https://reactome.org/content/detail/R-HSA-1169408) | curated |
| [Interferon alpha/beta signaling](https://reactome.org/content/detail/R-HSA-909733) | 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-10 signaling](https://reactome.org/content/detail/R-HSA-6783783) | curated |
| [Interleukin-2 signaling](https://reactome.org/content/detail/R-HSA-9020558) | 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-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 |
| [Interleukin-9 signaling](https://reactome.org/content/detail/R-HSA-8985947) | 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 |
| [Other interleukin signaling](https://reactome.org/content/detail/R-HSA-449836) | curated |
| [PD-L1(CD274) glycosylation and translocation to plasma membrane](https://reactome.org/content/detail/R-HSA-9931295) | curated |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [Activation of STAT3 by cadherin engagement](https://reactome.org/content/detail/R-HSA-9958825) | 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-15 signaling](https://reactome.org/content/detail/R-HSA-8983432) | electronic |
| [Interleukin-27 signaling](https://reactome.org/content/detail/R-HSA-9020956) | electronic |
| [Interleukin-6 signaling](https://reactome.org/content/detail/R-HSA-1059683) | electronic |
| [Interleukin-7 signaling](https://reactome.org/content/detail/R-HSA-1266695) | electronic |
| [Regulation of IFNA/IFNB signaling](https://reactome.org/content/detail/R-HSA-912694) | 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 |

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

**Molecular function:** protein tyrosine kinase activity, non-membrane spanning protein tyrosine kinase activity, protein phosphatase binding, ubiquitin protein ligase binding.

**Biological process:** protein phosphorylation, cell surface receptor signaling pathway via JAK-STAT, cytokine-mediated signaling pathway, positive regulation of homotypic cell-cell adhesion, interleukin-15-mediated signaling pathway, interleukin-4-mediated signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-12-31.

**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 | 2020-12-31 |

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

## Similar variants {#similar}

Related JAK1 variant pages (same residue, condition, or type): [JAK1 p.Ser22Phe](/variant/jak1-p-ser22phe), [JAK1 p.Arg1113Cys](/variant/jak1-p-arg1113cys), [JAK1 p.Arg1113His](/variant/jak1-p-arg1113his), [JAK1 p.Arg219Gln](/variant/jak1-p-arg219gln), [JAK1 p.Arg360Trp](/variant/jak1-p-arg360trp), [JAK1 p.Arg454Trp](/variant/jak1-p-arg454trp), [JAK1 p.Arg49Trp](/variant/jak1-p-arg49trp), [JAK1 p.Arg514Cys](/variant/jak1-p-arg514cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 1389135). 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.*