# NM_003177.7(SYK):c.328C>T (p.Pro110Ser)

https://sugi.bio/variant/syk-p-pro110ser

## Summary

**SYK p.Pro110Ser (c.328C>T)** is classified **Likely benign** in SYK (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-07). AlphaMissense: likely benign (0.3368); Ultra-rare (popmax 0.0103%, nfe).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0103%, nfe)

## For patients & families {#patients}

This is a change in the SYK gene that is classified as likely benign — not considered disease-causing, 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 | [SYK](https://sugi.bio/atlas/gene/SYK/) |
| Protein change (HGVS p.) | p.Pro110Ser |
| Coding change (HGVS c.) | c.328C>T |
| MANE Select transcript | [NM_003177](https://www.ncbi.nlm.nih.gov/nuccore/NM_003177) |
| Variant type | single nucleotide variant |
| Location | chr9:90844226-90844226 (GRCh38) |
| ClinVar | [VCV4848809](https://www.ncbi.nlm.nih.gov/clinvar/variation/4848809/) |

**All HGVS expressions:** `NC_000009.11:g.93606508C>T`, `NC_000009.12:g.90844226C>T`, `NG_017046.2:g.47497C>T`, `NM_001135052.4:c.328C>T`, `NM_001174167.3:c.328C>T`, `NM_001174168.3:c.328C>T`, `NM_003177.7:c.328C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.3368)
- REVEL 0.13 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -10.817 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense and REVEL do not
- Conservation: phyloP 7.501, GERP 1.78, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.6**. 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 0.74** across the covering region of the MANE Select transcript (90,843,899–90,874,683), spanning 30,784 bp. Chi-square p 7.2e-08. 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 (gnomAD v4.1): grpmax **0.0103%** (nfe) · FAF95 0.00884% · FAF99 0.00828% · 122/1,180,014 in the highest group · 133/1,614,194 alleles overall — ultra-rare (popmax 0.0103%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0103% | 9,672 |
| Remaining individuals (not grpmax-eligible) | 0.0096% | 10,418 |
| African / African-American | 0.004% | 25,021 |
| Admixed American | 0.00167% | 60,028 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,046 |

*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}

**SYK** population constraint: LOEUF 0.302, pLI 1, missense-Z 3.9545. *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 **110** lies in the 'interdomain a' region; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 84.52, 64% of residues very-high.

**93 experimental structure(s)** (PDB): [1A81](https://www.rcsb.org/structure/1A81), [1CSY](https://www.rcsb.org/structure/1CSY), [1CSZ](https://www.rcsb.org/structure/1CSZ), [1XBA](https://www.rcsb.org/structure/1XBA), [1XBB](https://www.rcsb.org/structure/1XBB), [1XBC](https://www.rcsb.org/structure/1XBC).

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

*Describes the biological roles of SYK (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:** SYK's established molecular role includes phosphotyrosine residue binding. p.Pro110Ser falls in the interdomain a region. In Reactome, SYK is annotated in disease pathway(s) including **FCGR3A-mediated IL10 synthesis**, **FCGR3A-mediated phagocytosis**.

**Disease mechanism (Reactome):** SYK loss or alteration is curated in [FCGR3A-mediated IL10 synthesis](https://reactome.org/content/detail/R-HSA-9664323), [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422), [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191).

### Pathways affected {#pathways}

SYK participates in **21 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [FCGR3A-mediated IL10 synthesis](https://reactome.org/content/detail/R-HSA-9664323) | curated |
| ⚕ [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422) | curated |
| ⚕ [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191) | curated |
| [DAP12 signaling](https://reactome.org/content/detail/R-HSA-2424491) | curated |
| [FCERI mediated MAPK activation](https://reactome.org/content/detail/R-HSA-2871796) | curated |
| [FLT3 signaling through SRC family kinases](https://reactome.org/content/detail/R-HSA-9706374) | curated |
| [Integrin signaling](https://reactome.org/content/detail/R-HSA-354192) | curated |
| [Interleukin-2 signaling](https://reactome.org/content/detail/R-HSA-9020558) | curated |
| [Regulation of actin dynamics for phagocytic cup formation](https://reactome.org/content/detail/R-HSA-2029482) | curated |
| [Role of phospholipids in phagocytosis](https://reactome.org/content/detail/R-HSA-2029485) | curated |
| [Antigen activates B Cell Receptor (BCR) leading to generation of second messengers](https://reactome.org/content/detail/R-HSA-983695) | electronic |
| [CLEC7A (Dectin-1) signaling](https://reactome.org/content/detail/R-HSA-5607764) | electronic |
| [Dectin-2 family](https://reactome.org/content/detail/R-HSA-5621480) | electronic |
| [FCERI mediated Ca+2 mobilization](https://reactome.org/content/detail/R-HSA-2871809) | electronic |
| [FCGR activation](https://reactome.org/content/detail/R-HSA-2029481) | electronic |
| [Fc epsilon receptor (FCERI) signaling](https://reactome.org/content/detail/R-HSA-2454202) | electronic |
| [GPVI-mediated activation cascade](https://reactome.org/content/detail/R-HSA-114604) | electronic |
| [Inactivation of CSF3 (G-CSF) signaling](https://reactome.org/content/detail/R-HSA-9705462) | electronic |
| [Regulation of signaling by CBL](https://reactome.org/content/detail/R-HSA-912631) | electronic |
| [Role of LAT2/NTAL/LAB on calcium mobilization](https://reactome.org/content/detail/R-HSA-2730905) | electronic |
| [Signaling by CSF3 (G-CSF)](https://reactome.org/content/detail/R-HSA-9674555) | electronic |

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

**Molecular function:** phosphotyrosine residue binding, protein kinase activity, protein serine/threonine kinase activity, protein tyrosine kinase activity, non-membrane spanning protein tyrosine kinase activity, signaling receptor binding.

**Biological process:** cell surface pattern recognition receptor signaling pathway, regulation of transcription by RNA polymerase II, protein phosphorylation, protein import into nucleus, leukocyte cell-cell adhesion, regulation of tumor necrosis factor-mediated signaling pathway.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-04-07.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-04-07 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related SYK variant pages (same residue, condition, or type): [SYK p.Glu473Gln](/variant/syk-p-glu473gln), [SYK c.1182-4G>A](/variant/syk-c-1182-minus-4g-a), [SYK c.1182-7C>A](/variant/syk-c-1182-minus-7c-a), [SYK c.1182-7C>G](/variant/syk-c-1182-minus-7c-g), [SYK c.1582-16T>A](/variant/syk-c-1582-minus-16t-a), [SYK c.796+20G>C](/variant/syk-c-796-plus-20g-c), [SYK p.Arg434=](/variant/syk-p-arg434), [SYK p.Asn499=](/variant/syk-p-asn499).

### 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 4848809). 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.*