# NM_006950.3(SYN1):c.1972C>T (p.Pro658Ser)

https://sugi.bio/variant/syn1-p-pro658ser

## Summary

**SYN1 p.Pro658Ser (c.1972C>T)** is classified **Uncertain significance** in SYN1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-04-15). AlphaMissense: likely benign (0.2352); Very rare (popmax 0.00269%, amr); Associated with epilepsy, X-linked 1, with variable learning disabilities and behavior disorders.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs755832757 · 3 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00269%, amr)

## For patients & families {#patients}

This is a change in the SYN1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, 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.Pro658Ser |
| Coding change (HGVS c.) | c.1972C>T |
| MANE Select transcript | [NM_006950](https://www.ncbi.nlm.nih.gov/nuccore/NM_006950) |
| dbSNP | [rs755832757](https://www.ncbi.nlm.nih.gov/snp/rs755832757/) |
| Variant type | single nucleotide variant |
| Location | chrX:47574012-47574012 (GRCh38) |
| ClinVar | [VCV954219](https://www.ncbi.nlm.nih.gov/clinvar/variation/954219/) |

**All HGVS expressions:** `NC_000023.10:g.47433411G>A`, `NC_000023.11:g.47574012G>A`, `NG_008437.1:g.50846C>T`, `NM_006950.3:c.1972C>T`, `NM_133499.2:c.1972C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2352)
- REVEL 0.286 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.162 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 11.283, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.7**. 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 0.82** across the covering region of the MANE Select transcript (47,572,867–47,574,350), spanning 1,483 bp. Chi-square p 0.025. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 SYN1 (546 scored positions, the nearest 6 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 **0.00269%** (amr) · 1/37,166 in the highest group · 1/1,144,627 alleles overall — very rare (popmax 0.00269%, amr).

*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 **658** 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 'e' 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-04-15.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2022–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-10-07 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-05-05 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-04-15 |

## 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/), [intellectual disability, X-linked 50](https://sugi.bio/atlas/disease/intellectual-disability-x-linked-50/).

**Reported phenotype names (ClinVar):** Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders, Intellectual disability, X-linked 50, not provided, X-linked epilepsy-learning disabilities-behavior disorders syndrome, INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED 50, MRX50, none provided.

## Similar variants {#similar}

Related SYN1 variant pages (same residue, condition, or type): [SYN1 c.528-2A>T](/variant/syn1-c-528-minus-2a-t), [SYN1 c.838-2A>G](/variant/syn1-c-838-minus-2a-g), [SYN1 p.Arg234Ter](/variant/syn1-p-arg234ter), [SYN1 p.Arg420Gln](/variant/syn1-p-arg420gln), [SYN1 p.Arg422Ter](/variant/syn1-p-arg422ter), [SYN1 p.Gln249Ter](/variant/syn1-p-gln249ter), [SYN1 p.Gln483Ter](/variant/syn1-p-gln483ter), [SYN1 p.Gln555Ter](/variant/syn1-p-gln555ter).

### 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 954219). 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.*