# NM_003331.5(TYK2):c.741G>A (p.Pro247=)

https://sugi.bio/variant/tyk2-p-pro247

## Summary

**TYK2 p.Pro247= (c.741G>A)** is classified **Likely benign** in TYK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-24). Ultra-rare (popmax 0.0107%, afr); Associated with immunodeficiency 35.

**At a glance:** Likely benign · review: Single submitter · rsID rs377117351 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0107%, afr)

## For patients & families {#patients}

This is a change in the TYK2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to immunodeficiency 35.

*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 recessive |
| Age of onset (of this condition) | Infancy |
| Diagnostic panels | TYK2 is a diagnostic-grade gene on 2 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017514/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TYK2](https://sugi.bio/atlas/gene/TYK2/) |
| Protein change (HGVS p.) | p.Pro247= |
| Coding change (HGVS c.) | c.741G>A |
| MANE Select transcript | [NM_003331](https://www.ncbi.nlm.nih.gov/nuccore/NM_003331) |
| dbSNP | [rs377117351](https://www.ncbi.nlm.nih.gov/snp/rs377117351/) |
| Variant type | single nucleotide variant |
| Location | chr19:10365787-10365787 (GRCh38) |
| ClinVar | [VCV2080609](https://www.ncbi.nlm.nih.gov/clinvar/variation/2080609/) |

**All HGVS expressions:** `LRG_121:g.19786G>A`, `LRG_121t1:c.741G>A`, `NC_000019.10:g.10365787C>T`, `NC_000019.9:g.10476463C>T`, `NG_007872.1:g.19786G>A`, `NM_001385197.1:c.741G>A`, `NM_001385198.1:c.741G>A`, `NM_001385199.1:c.741G>A`, `NM_001385200.1:c.741G>A`, `NM_001385201.1:c.741G>A`, `NM_001385202.1:c.741G>A`, `NM_001385203.1:c.741G>A`, `NM_001385204.1:c.741G>A`, `NM_001385205.1:c.651G>A`, `NM_001385206.1:c.741G>A`, `NM_001385207.1:c.741G>A`, `NM_001406461.1:c.741G>A`, `NM_003331.5:c.741G>A`

## 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 -20, GERP -3.93 — fast-evolving / accelerated position
- CADD: **PHRED 0.59**. 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 TYK2 (1,423 scored positions, the nearest 17 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 **0.0107%** (afr) · FAF95 0.00528% · FAF99 0.00381% · 8/74,928 in the highest group · 28/1,612,154 alleles overall — ultra-rare (popmax 0.0107%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0107% | 9,366 |
| South Asian | 0.0022% | 45,507 |
| European (non-Finnish) | 0.00153% | 65,540 |

*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}

**TYK2** population constraint: LOEUF 0.626, pLI 1.5716e-07, missense-Z 2.042. *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 **247** lies in the ferm domain; a turn.

AlphaFold model confidence (whole protein): pLDDT 82.69, 53% of residues very-high.

**52 experimental structure(s)** (PDB): [3LXN](https://www.rcsb.org/structure/3LXN), [3LXP](https://www.rcsb.org/structure/3LXP), [3NYX](https://www.rcsb.org/structure/3NYX), [3NZ0](https://www.rcsb.org/structure/3NZ0), [3ZON](https://www.rcsb.org/structure/3ZON), [4GFO](https://www.rcsb.org/structure/4GFO).

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

*Describes the biological roles of TYK2 (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:** TYK2's established molecular role includes protein tyrosine kinase activity. p.Pro247= falls in the ferm domain. In Reactome, TYK2 is annotated in disease pathway(s) including **Evasion by RSV of host interferon responses**, **Potential therapeutics for SARS**.

**Disease mechanism (Reactome):** TYK2 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}

TYK2 participates in **21 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 |
| ⚕ [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370) | curated |
| [IL-6-type cytokine receptor ligand interactions](https://reactome.org/content/detail/R-HSA-6788467) | curated |
| [Interferon alpha/beta signaling](https://reactome.org/content/detail/R-HSA-909733) | curated |
| [Interleukin-10 signaling](https://reactome.org/content/detail/R-HSA-6783783) | 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 |
| [Other interleukin signaling](https://reactome.org/content/detail/R-HSA-449836) | 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-23 signaling](https://reactome.org/content/detail/R-HSA-9020933) | 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 |
| [Regulation of IFNA/IFNB signaling](https://reactome.org/content/detail/R-HSA-912694) | 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, growth hormone receptor binding.

**Biological process:** cell surface receptor signaling pathway via JAK-STAT, interleukin-12-mediated signaling pathway, interleukin-23-mediated signaling pathway, type II interferon-mediated signaling pathway, type I interferon-mediated signaling pathway, interleukin-10-mediated signaling pathway.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-24.

**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 | 2024-10-24 |

## Associated conditions {#conditions}

[immunodeficiency 35](https://sugi.bio/atlas/disease/immunodeficiency-35/).

**Reported phenotype names (ClinVar):** Immunodeficiency 35, TYK2 DEFICIENCY, HIES WITH ATYPICAL MYCOBACTERIOSIS, AUTOSOMAL RECESSIVE, HYPER-IgE SYNDROME WITH ATYPICAL MYCOBACTERIOSIS, AUTOSOMAL RECESSIVE, Susceptibility to infection due to TYK2 deficiency.

## Similar variants {#similar}

Related TYK2 variant pages (same residue, condition, or type): [TYK2 p.Pro247Gln](/variant/tyk2-p-pro247gln), [TYK2 p.Pro247Leu](/variant/tyk2-p-pro247leu), [TYK2 p.Pro247Ser](/variant/tyk2-p-pro247ser), [TYK2 p.Arg609Ter](/variant/tyk2-p-arg609ter), [TYK2 p.Trp798Ter](/variant/tyk2-p-trp798ter), [TYK2 p.Ala1004Gly](/variant/tyk2-p-ala1004gly), [TYK2 p.Ala1026Thr](/variant/tyk2-p-ala1026thr), [TYK2 p.Ala165Thr](/variant/tyk2-p-ala165thr).

### 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 2080609). 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.*