# NM_006950.3(SYN1):c.1962del (p.Pro655fs)

https://sugi.bio/variant/syn1-p-pro655fs

## Summary

**SYN1 p.Pro655fs (c.1962del)** is classified **Likely pathogenic** in SYN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-11-01). Very rare (popmax 0.000115%, nfe).

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs1556857412 · 1 submitter · very rare (popmax 0.000115%, nfe)

## For patients & families {#patients}

This is a change in the SYN1 gene that is considered likely 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 | [SYN1](https://sugi.bio/atlas/gene/SYN1/) |
| Protein change (HGVS p.) | p.Pro655fs |
| Coding change (HGVS c.) | c.1962del |
| MANE Select transcript | [NM_006950](https://www.ncbi.nlm.nih.gov/nuccore/NM_006950) |
| dbSNP | [rs1556857412](https://www.ncbi.nlm.nih.gov/snp/rs1556857412/) |
| Variant type | Deletion |
| Location | chrX:47574022-47574022 (GRCh38) |
| ClinVar | [VCV547077](https://www.ncbi.nlm.nih.gov/clinvar/variation/547077/) |

**All HGVS expressions:** `NC_000023.10:g.47433421del`, `NC_000023.11:g.47574022del`, `NG_008437.1:g.50836del`, `NM_006950.3:c.1962del`, `NM_133499.2:c.1962del`

## Computational & population evidence {#evidence}

- 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 **within the last 50 nt of the penultimate exon (12 of 13, 20 nt from its 3' end)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- 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 (gnomAD v4.1): grpmax **0.000115%** (nfe) · 1/869,236 in the highest group · 1/1,149,102 alleles overall — very rare (popmax 0.000115%, nfe).

*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 **655** lies in the 'disordered' region; a UniProt-annotated variant site (in xlid50; affects excitatory and inhibitory synaptic transmission leading to neuronal hyperexcitability; fails to rescue defective synaptic vesicle exocytosis in syn1-knockout mouse neurons; results in severely decreased phosphorylation by camk2 and mapk1; results in delayed axon elongation when tested in syn1-knockout mouse neurons; severely reduced interaction with syn2; has no effect on protein targeting to presynapse); the 'd; pro-rich 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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2017-11-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Likely pathogenic | criteria provided, single submitter | clinical testing | 2017-11-01 |

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

## Similar variants {#similar}

Related SYN1 variant pages (same residue, condition, or type): [SYN1 p.Pro655Leu](/variant/syn1-p-pro655leu), [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 c.980+43_981del](/variant/syn1-c-980-plus-43-981del), [SYN1 p.Ala577fs](/variant/syn1-p-ala577fs), [SYN1 p.Ala676fs](/variant/syn1-p-ala676fs).

### 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 547077). 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.*