# NM_006950.3(SYN1):c.98_114del (p.Pro33fs)

https://sugi.bio/variant/syn1-p-pro33fs

## Summary

**SYN1 p.Pro33fs (c.98_114del)** is classified **Pathogenic** in SYN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-07). No gnomAD frequency available for this variant; Associated with epilepsy, X-linked 1, with variable learning disabilities and behavior disorders.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2519712469 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the SYN1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to epilepsy, X-linked 1, with variable learning disabilities and behavior disorders.

*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) | X-linked recessive |
| Age of onset (of this condition) | Childhood |
| Diagnostic panels | SYN1 is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of X-linked epilepsy-learning disabilities-behavior disorders syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Macrocephaly — Very frequent (99-80%)
- Aggressive behavior — Very frequent (99-80%)
- Seizure — Very frequent (99-80%)
- Specific learning disability — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016748/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SYN1](https://sugi.bio/atlas/gene/SYN1/) |
| Protein change (HGVS p.) | p.Pro33fs |
| Coding change (HGVS c.) | c.98_114del |
| MANE Select transcript | [NM_006950](https://www.ncbi.nlm.nih.gov/nuccore/NM_006950) |
| dbSNP | [rs2519712469](https://www.ncbi.nlm.nih.gov/snp/rs2519712469/) |
| Variant type | Deletion |
| Location | chrX:47619615-47619631 (GRCh38) |
| ClinVar | [VCV2766607](https://www.ncbi.nlm.nih.gov/clinvar/variation/2766607/) |

**All HGVS expressions:** `NC_000023.10:g.47479019_47479035del`, `NC_000023.11:g.47619620_47619636del`, `NG_008437.1:g.5227_5243del`, `NM_006950.3:c.98_114del`, `NM_133499.2:c.98_114del`

## 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 1.635, GERP -0.038, phastCons 1 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 13**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**SYN1** population constraint: ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **X-linked complex neurodevelopmental disorder** — Definitive (XL)

## Protein context {#protein}

Residue **33** lies in the 'disordered' region; the 'b; linker' region.

AlphaFold model confidence (whole protein): pLDDT 69.86, 44% of residues very-high.

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

*Describes the biological roles of SYN1 (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.*


### Pathways affected {#pathways}

SYN1 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Dopamine Neurotransmitter Release Cycle](https://reactome.org/content/detail/R-HSA-212676) | curated |
| [Serotonin Neurotransmitter Release Cycle](https://reactome.org/content/detail/R-HSA-181429) | curated |
| [Sensory processing of sound by inner hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662360) | electronic |

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

**Biological process:** regulation of synaptic vesicle exocytosis.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-10-07.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-10-07 |

## Associated conditions {#conditions}

[epilepsy, X-linked 1, with variable learning disabilities and behavior disorders](https://sugi.bio/atlas/disease/epilepsy-x-linked-1-with-variable-learning-disabilities-and-behavior-disorders/).

**Reported phenotype names (ClinVar):** Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders, X-linked epilepsy-learning disabilities-behavior disorders syndrome.

## Similar variants {#similar}

Related SYN1 variant pages (same residue, condition, or type): [SYN1 p.Pro33Gln](/variant/syn1-p-pro33gln), [SYN1 p.Asn334fs](/variant/syn1-p-asn334fs), [SYN1 p.Met1fs](/variant/syn1-p-met1fs), [SYN1 p.His38_Ala42del](/variant/syn1-p-his38-ala42del), [SYN1 c.1056-14_1056-8del](/variant/syn1-c-1056-minus-14-1056-minus-8del), [SYN1 p.Ala577fs](/variant/syn1-p-ala577fs), [SYN1 p.Ala83fs](/variant/syn1-p-ala83fs), [SYN1 p.Arg430fs](/variant/syn1-p-arg430fs).

### 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 2766607). 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.*